Compounds and compositions as protein kinase inhibitors

ABSTRACT

The present invention provides compounds of Formula I or II: 
                         
wherein R 1 , R 1b , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are defined herein. The compounds of Formula (I) or (II) and pharmaceutical compositions thereof are useful for the treatment of B-Raf-associated diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 13/473, 230, filedMay 15, 2012, which is a divisional of 12/862,418, filed Aug. 24, 2012,which issued as U.S. Pat. No. 8,242,260, and claims the benefit ofpriority under 35 U.S.C. §119(e) to U.S. provisional application Ser.No. 61/238,083, filed on Aug. 28, 2009, and U.S. provisional applicationSer. No. 61/313,061, filed on Mar. 11, 2010, which are incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

The invention provides a novel class of compounds, pharmaceuticalcompositions comprising such compounds and methods of using suchcompounds to treat or prevent diseases or disorders associated withabnormal or deregulated kinase activity, particularly diseases ordisorders that involve abnormal activation of B-Raf.

BACKGROUND OF THE INVENTION

The protein kinases represent a large family of proteins, which play acentral role in the regulation of a wide variety of cellular processesand maintaining control over cellular function. A partial, non-limiting,list of these kinases include: receptor tyrosine kinases such asplatelet-derived growth factor receptor kinase (PDGF-R), the nervegrowth factor receptor, trkB, Met, and the fibroblast growth factorreceptor, FGFR3; non-receptor tyrosine kinases such Abl and the fusionkinase BCR-Ab1, Lck, Csk, Fes, Bmx and c-src; and serine/threoninekinases such as B-Raf, sgk, MAP kinases (e.g., MKK4, MKK6, etc.) andSAPK2α, SAPK2β and SAPK3. Aberrant kinase activity has been observed inmany disease states including benign and malignant proliferativedisorders as well as diseases resulting from inappropriate activation ofthe immune and nervous systems.

SUMMARY

Compounds of Formula (I) and (II) below are described herein which havebeen shown to have Raf kinase activity:

whereinR¹ is(i) H,(ii) (C₃-C₆) cycloalkyl optionally substituted with cyano;(iii) (C₁-C₃) alkyl optionally substituted with cyano, —C(O)NH₂, orhydroxy, or(iv) —X¹NHC(O)OR^(1a) or —X¹NHC(O)NHR^(1a), where X¹ is (C₁-C₄)alkyleneoptionally substituted with 1 to 3 groups each independently selectedfrom halo, (C₁-C₄)alkyl, or halosubstituted(C₁-C₄)alkyl and R^(1a) is H,(C₁-C₄)alkyl, or halosubstituted(C₁-C₄)alkyl;R^(1b) is H or methyl;R² is H or halogen;R³ is H, halogen, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,halosubstituted(C₁-C₄)alkoxy, or halosubstituted(C₁-C₄)alkyl;R⁴ is halogen, H, or (C₁-C₄) alkyl;R⁵ is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₈)branched alkyl,halosubstituted(C₁-C₆)alkyl, halosubstituted(C₃-C₈)branched alkyl,(C₃-C₆)cycloalkyl(C₁-C₃)alkylene, or phenyl, where said phenyl isoptionally substituted with 1 to 3 substituents each independentlyselected form halo, CH₃, or CF₃;R⁶ is H, (C₁-C₄) alkyl, or halogen; andR⁷ is H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, 1-methyl-(C₃-C₆)cycloalkyl,1-(halosubstituted methyl)-(C₃-C₆)cycloalkyl, —(C₃-C₈)branched alkyl,halosubstituted(C₁-C₆)alkyl, halosubstituted(C₃-C₈)branched alkyl, orphenyl, where said phenyl is optionally substituted with 1 to 3substituents selected form halogen, (C₁-C₄)alkyl orhalosubstituted(C₁-C₄)alkyl, preferably R⁷ is H, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, 1-methyl-(C₃-C₆)cycloalkyl, (C₃-C₈)branched alkyl, orphenyl, where said phenyl is optionally substituted with 1 to 3substituents selected form halogen, (C₁-C₄)alkyl orhalosubstituted(C₁-C₄)alkyl; or a pharmaceutically acceptable saltthereof.

In one embodiment, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, is provided.

In one particular embodiment of a compound of Formula I

R¹ is

(i) (C₁-C₃)alkyl optionally substituted with cyano, —C(O)NH₂, orhydroxy, or

(ii) —X¹NHC(O)OR^(1a), where X¹ is (C₁-C₄)alkylene optionallysubstituted with 1 to 3 groups each independently selected from halo,(C₁-C₄)alkyl, or halosubstituted(C₁-C₄)alkyl and R^(1a) is H,(C₁-C₄)alkyl, or halosubstituted(C₁-C₄)alkyl;

R² is H or halogen;

R³ is H, halogen, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,halosubstituted(C₁-C₄)alkoxy, or halosubstituted(C₁-C₄)alkyl;

R⁴ is halogen, H, or (C₁-C₄)alkyl;

R⁵ is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₈)branched alkyl,halosubstituted(C₁-C₆)alkyl, or halosubstituted(C₃-C₈)branched alkyl;

R⁶ is H, (C₁-C₄)alkyl, or halogen; and

R⁷ is H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, 1-methyl-(C₃-C₆)cycloalkyl,1-(halosubstituted methyl)-(C₃-C₆)cycloalkyl, (C₃-C₈)branched alkyl,halosubstituted(C₁-C₆)alkyl, or halosubstituted(C₃-C₈)branched alkyl orphenyl, where said phenyl is optionally substituted with 1 to 3substituents selected form halogen, (C₁-C₄)alkyl orhalosubstituted(C₁-C₄)alkyl, preferably R⁷ is H, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, 1-methyl-(C₃-C₆)cycloalkyl, or phenyl, where saidphenyl is optionally substituted with 1 to 3 substituents selected formhalogen, (C₁-C₄)alkyl or halosubstituted(C₁-C₄)alkyl; or apharmaceutically acceptable salt thereof.

In one preferred embodiment, compounds of Formula (I) are providedwherein R¹ is —X¹NHC(O)OR^(1a), where X¹ is a (C₁-C₄)alkylene optionallysubstituted with 1 to 3 groups each independently selected from(C₁-C₄)alkyl or halosubstituted(C₁-C₄)alkyl and R^(1a) is (C₁-C₂)alkylor halosubstituted(C₁-C₂)alkyl; R² is H or F; R³ is H, halogen,(C₁-C₂)alkoxy, (C₁-C₂)alkyl, halosubstituted(C₁-C₂)alkoxy, orhalosubstituted(C₁-C₂)alkyl; R⁴ is H or methyl; R⁵ is (C₁-C₄)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₅)branched alkyl, halosubstituted(C₁-C₄)alkyl,or halosubstituted(C₃-C₆)branched alkyl; R⁶ is H, (C₁-C₂)alkyl, orhalogen; and R⁷ is (C₃-C₆)cycloalkyl, 1-methyl-(C₃-C₆)cycloalkyl, or(C₃-C₆)branched alkyl; or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, compounds of Formula (I) are providedwherein R¹ is —X¹NHC(O)OR^(1a), where X¹ is a (C₁-C₄)alkylene optionallysubstituted with 1 to 3 groups each independently selected from(C₁-C₄)alkyl or halosubstituted(C₁-C₄)alkyl and R^(1a) is (C₁-C₂)alkylor halosubstituted(C₁-C₂)alkyl; R² is H or F; R³ is H, halogen,(C₁-C₂)alkoxy, (C₁-C₂)alkyl, halosubstituted(C₁-C₂)alkoxy, orhalosubstituted(C₁-C₂)alkyl; R⁴ is H or methyl; R⁵ is (C₁-C₄)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₅)branched alkyl, halosubstituted(C₁-C₄)alkyl,halosubstituted(C₃-C₆)branched alkyl, (C₃-C₆)cycloalkyl(C₁-C₃)alkylene,or phenyl substituted with 1 to 3 substituents each independentlyselected form Cl, F, CH₃, or CF₃; R⁶ is H, (C₁-C₂)alkyl, or halogen; andR⁷ is (C₃-C₆)cycloalkyl, 1-methyl-(C₃-C₆)cycloalkyl, or (C₃-C₆)branchedalkyl; or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, compounds of Formula (I) are providedwherein R¹ is —X¹NHC(O)OR^(1a), where X¹ is (C₁-C₂)alkylene substitutedwith (C₁-C₂)alkyl and R^(1a) is (C₁-C₂)alkyl; R² is H; R³ is H, Cl, F,methoxy, methyl, or difluoromethoxy; R⁴ is H; R⁵ is methyl, cyclopropyl,ethyl, propyl, isopropyl, sec-butyl, isobutyl, trifluoromethyl, or3,3,3-trifluoropropyl; R⁶ is H, methyl, F, or Cl; and R⁷ is t-butyl,cyclopropyl, or 1-trifluoromethylcyclopropyl; or a pharmaceuticallyacceptable salt thereof.

In another preferred embodiment, compounds of Formula (I) are providedwherein R¹ is —X¹NHC(O)OR^(1a), where X¹ is a (C₁-C₄)alkylene optionallysubstituted with 1 to 3 groups each independently selected from(C₁-C₄)alkyl or halosubstituted(C₁-C₄)alkyl and R^(1a) is (C₁-C₂)alkylor halosubstituted(C₁-C₂)alkyl; R² is H or F; R³ is H, halogen,(C₁-C₂)alkoxy, (C₁-C₂)alkyl, halosubstituted(C₁-C₂)alkoxy, orhalosubstituted(C₁-C₂)alkyl; R⁴ is H or methyl; R⁵ is (C₁-C₄)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₅)branched alkyl, halosubstituted(C₁-C₄)alkyl,halosubstituted(C₃-C₆)branched alkyl, or phenyl substituted with F, CH₃,or CF₃; R⁶ is H, (C₁-C₂)alkyl, or halogen; and R⁷ is (C₃-C₆)cycloalkyl,1-methyl-(C₃-C₆)cycloalkyl, or (C₃-C₆)branched alkyl; or apharmaceutically acceptable salt thereof.

In yet another preferred embodiment, compounds of Formula (I) areprovided wherein R¹ is —X¹NHC(O)OR^(1a), where X¹ is (C₁-C₂)alkylenesubstituted with (C₁-C₂)alkyl and R^(1a) is (C₁-C₂)alkyl; R² is H; R³ isH, Cl, F, methoxy, methyl, or difluoromethoxy; R⁴ is H; R⁵ is methyl,cyclopropyl, ethyl, propyl, isopropyl, sec-butyl, isobutyl,trifluoromethyl, or 3,3,3-trifluoropropyl; R⁶ is H, methyl, F, or Cl;and R⁷ is t-butyl, cyclopropyl, or 1-methylcyclopropyl; or apharmaceutically acceptable salt thereof.

In one embodiment, compounds of Formula (II), or a pharmaceuticallyacceptable salt thereof.

In a preferred embodiment, compounds of Formula (II) are providedwherein R² is H or F; R³ is H, halogen, (C₁-C₂)alkoxy, (C₁-C₂)alkyl,halosubstituted(C₁-C₂)alkoxy, or halosubstituted(C₁-C₂)alkyl; R⁴ is H ormethyl; R⁵ is (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₅)branched alkyl,halosubstituted(C₁-C₄)alkyl, halosubstituted(C₃-C₆)branched alkyl, or(C₃-C₆)cycloalkyl(C₁-C₃)alkylene; R⁶ is H, (C₁-C₂)alkyl, or halogen; andR² is (C₃-C₆)cycloalkyl, 1-methyl-(C₃-C₆)cycloalkyl, or (C₃-C₆)branchedalkyl; or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, compounds of Formula (II) are providedwherein R² is H; R³ is H, Cl, F, methoxy, methyl, or difluoromethoxy; R⁴is H; R⁵ is methyl, cyclopropyl, ethyl, propyl, isopropyl, sec-butyl,isobutyl, trifluoromethyl, or 3,3,3-trifluoropropyl; R⁶ is H, methyl, F,or Cl; and R⁷ is t-butyl, cyclopropyl, or 1-methylcyclopropyl; or apharmaceutically acceptable salt thereof.

In one preferred embodiment, compounds of Formula (I) or (II) areprovided wherein R¹ has the following formula (1a)

or a pharmaceutically acceptable salt thereof.

Particular compounds of Formula (I) include: (S)-Methyl1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(R)-Methyl1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(2-cyclopropyl-4-(2-fluoro-5-methyl-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(2-cyclopropyl-4-(2,5-dichloro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(4-(2-chloro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(2-cyclopropyl-4-(2-fluoro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;Methyl(2S)-1-(4-(2-cyclopropyl-4-(2,5-difluoro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;and (S)-Methyl1-(4-(4-(2-chloro-5-methyl-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;or a pharmaceutically acceptable salt thereof. In particular, (S)-Methyl1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate,or a pharmaceutically acceptable salt thereof.

Other particular compounds of Formula (I) include: (S)-Methyl1-(4-(5-(5-chloro-3-(cyclopropanesulfonamido)-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(5-(5-chloro-3-(ethylsulfonamido)-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(5-(5-chloro-2-fluoro-3-(3,3,3-trifluoropropylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(5-(5-chloro-3-(cyclopropylmethylsulfonamido)-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(4-(2-chloro-3-(ethylsulfonamido)-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(4-(2-chloro-3-(cyclopropanesulfonamido)-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(5-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(5-(2-fluoro-5-methyl-3-(methylsulfonamido)phenyl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(5-(5-chloro-2-fluoro-3-(4-fluorophenylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;and (S)-Methyl1-(4-(5-(5-chloro-2-fluoro-3-(3-fluorophenylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;or a pharmaceutically acceptable salt thereof.

Particular compounds of Formula (II) includeN-(2-chloro-3-(2-cyclopropyl-5-(pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)-2,6-difluorobenzenesulfonamide;N-(2-chloro-3-(2-cyclopropyl-5-(pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide;andN-(2-chloro-3-(2-cyclopropyl-5-(pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)propane-1-sulfonamide;or a pharmaceutically acceptable salt thereof.

The compounds of the present invention inhibit the activity of B-Raf andare, therefore, expected to be useful in the treatment ofB-Raf-associated diseases.

In another aspect of the present invention, a pharmaceutical compositionis provided which comprises a compound of Formula (I), or apharmaceutically acceptable salt thereof, and a diluent, carrier orexcipient. The pharmaceutical composition may further comprise anadditional therapeutic agent, wherein the additional therapeutic agentis selected from the group consisting of an anticancer compound, ananalgesic, an antiemetic, an antidepressant, and an anti-inflammatoryagent.

In yet another aspect of the present invention, a method for treatingcancer is provided which comprises administering to a subject in need ofsuch treatment a pharmaceutically effective amount of a compound ofFormula (I), or a pharmaceutical acceptable salt thereof, or apharmaceutical composition comprising a compound of Formula (I), or apharmaceutical acceptable salt thereof, and a diluent, carrier orexcipient.

In another aspect of the present invention, a method for treating acondition mediated by Raf kinase which comprises administering to asubject in need thereof an effective amount of a compound of Formula(I), or a pharmaceutical acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticalacceptable salt thereof, and a diluent, carrier or excipient.Preferably, the Raf Kinase being mediated is a mutant b-Raf kinase, morepreferably, a mutant b-Raf(V600E) kinase.

The methods may comprise administering an additional therapeutic agent.Preferred additional agents include an anticancer drug, a painmedication, an antiemetic, an antidepressant or an anti-inflammatoryagent, more preferably, the additional therapeutic agent is a differentRaf kinase inhibitor or an inhibitor of MEK, mTOR, PI3K, CDK9, PAK,Protein Kinase C, a MAP kinase, a MAPK Kinase, or ERK.

DEFINITIONS

“Alkyl” as a group and as a structural element of other groups, forexample halo-substituted-alkyl and alkoxy, can be eitherstraight-chained or branched. C₁₋₄-alkoxy includes, methoxy, ethoxy, andthe like. “Halosubstituted alkyl” refers to an alkyl group (branched orunbranched) wherein any of the hydrogens can be substituted with ahalogen. Representative examples of halosubstituted-(C₁-C₄)alkyl includefluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl,difluoroethyl, pentafluoroethyl, and the like. Similarly,hydroxy-substituted-(C₁-C₆)alkyl means and alkyl group (branched orunbranched) wherein any of the hydrogens can be substituted with ahydroxyl. For example, hydroxy-substituted-(C₁-C₆)alkyl includes2-hydroxyethyl, and the like. Similarly, cyano-substituted-(C₁-C₆)alkylmeans and alkyl group (branched or unbranched) wherein any of thehydrogens can be substituted with cyano.

“Aryl” means a monocyclic or fused bicyclic aromatic ring assemblycontaining six to ten ring carbon atoms. For example, aryl may be phenylor naphthyl, preferably phenyl. “Arylene” means a divalent radicalderived from an aryl group.

“Heteroaryl” is as defined for aryl above where one or more of the ringmembers is a heteroatom. For example, (C₁-C₁₀)heteroaryl includespyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl,benzopyranyl, benzothiopyranyl, benzo[1,3]dioxole, imidazolyl,benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl,tetrazolyl, pyrazolyl, thienyl, etc.

“Cycloalkyl” means a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing the numberof ring atoms indicated. For example, (C₃-C₁₀)cycloalkyl includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, and cyclodecyl. A preferred cycloalkyl iscyclopropyl.

“Heterocycloalkyl” means cycloalkyl where one or more of the ringcarbons is replaced by a moiety selected from —O—, —N═, —NR—, —C(O)—,—S—, —S(O)— or —S(O)₂—, wherein R is hydrogen, (C₁-C₄)alkyl or anitrogen protecting group (—NPg). Representative examples of(C₃-C₈)heterocycloalkyl include 2H-pyranyl, 4H-pyranyl, piperidinyl,1,4-dioxane, morpholinyl, 1,4-dithianyl, thiomorpholino,imidazolidin-2-one, tetrahydrofuran, piperazinyl, 1,3,5-trithianyl,pyrrolidinyl, pyrrolidinyl-2-one, piperidinone,1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, etc.

“Halogen” (or halo) represents chloro, fluoro, bromo or iodo.

“Treat”, “treating” and “treatment” refer to a method of alleviating orabating a disease and/or its attendant symptoms.

The term “compounds of the present invention” (unless specificallyidentified otherwise) refer to compounds of Formula (I) or (II),prodrugs thereof, pharmaceutically acceptable salts of the compounds,and/or prodrugs, and hydrates or solvates of the compounds, salts,and/or prodrugs, as well as, all stereoisomers (includingdiastereoisomers and enantiomers), tautomers and isotopically labeledcompounds.

DETAILED DESCRIPTION

Compounds of the present invention may be synthesized by syntheticroutes that include processes analogous to those well-known in thechemical arts, particularly in light of the description containedherein. The starting materials are generally available from commercialsources such as Aldrich Chemicals (Milwaukee, Wis.) or are readilyprepared using methods well known to those skilled in the art (e.g.,prepared by methods generally described in Louis F. Fieser and MaryFieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York(1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl.ed. Springer-Verlag, Berlin, including supplements (also available viathe Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below providepotential routes for synthesizing the compounds of the present inventionas well as key intermediates. For a more detailed description of theindividual reaction steps, see the Examples section below. Those skilledin the art will appreciate that other synthetic routes may be used tosynthesize the inventive compounds. Although specific starting materialsand reagents are depicted in the schemes and discussed below, otherstarting materials and reagents can be easily substituted to provide avariety of derivatives and/or reaction conditions. In addition, many ofthe compounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Compounds of Formula I can be prepared using the procedure outlined inScheme I below.

The dibromo imidazole intermediate (1a) may by prepared by condensingthe desired aldehyde (R⁷C(O)H) with glyoxal in the presence of ammoniumhydroxide at a temperature from about 0° C. to about 5° C. to afford theC-2 substituted imidazole (see e.g., J Med Chem, (1979), 22, 687),followed by bromination. Deprotonation with NaH, and addition of anamino-protection group (e.g., 2-(trimethylsilyl)ethoxymethyl chloride(SEMCl) would furnish the protected dibromo imidazole (1b). Thoseskilled in the art will appreciate that other nitrogen protecting groupsmay be employed instead of the SEM protecting group. Directedlithiation, followed by addition into 2-chloropyrimidine and subsequentoxidation can provide the 5-(2-chloro-4-pyrimidinyl)-4-bromoimidazole(1c). See, Organic Letters 2005, 7, 4133. Simple SnAr substitution withthe desired amine (R¹NH) can afford substituted pyrimidines (1d). SEMdeprotection (e.g., HCl in protic solvent, such as ethanol, etc.) toafford intermediate (1e) and subsequent Suzuki cross-coupling with thedesired sulfonanilide boronate ester or acid (1f) would provideintermediate (1g). The final cross-coupling may be generally substitutedwith the corresponding Stille reactions where the boronate ester or acidis replaced with the corresponding stannane. The desired sulfonylchloride may then be added to the primary amine group of intermediate(1g) in the presence of a base (e.g., pyridine) to produce a compound ofFormula (I).

Compounds of Formula I or II can also be prepared by the proceduresoutlined below in Scheme II.

Reversing the order of cross-coupling and deprotection from Scheme Iwould yield the trisubstituted imidazole (1g). Removal of the imidazoleprotecting could also be reserved to the end of the synthetic sequence.Treatment with the desired sulfonyl chloride (R⁵SO₂Cl) in the presenceof pyridine at reduced temperatures produces a compound of Formula (I).

Another alternative route for making compounds of the present inventionis outlined in Scheme III below.

In a variation of the route described in Scheme I, the bromoimidazoleintermediate (1c) may be cross-coupled with the appropriate boronateester or (1f) to provide the3-(5-(2-chloropyrimidin-4-yl)-1H-imidazol-4-yl)aniline (3a). Treatmentwith the desired sulfonyl chloride will furnish the correspondingsulfonanilide (3b). Simple SnAr substitution with the desired amine(R¹NH) can afford substituted pyrimidines (3c) and deprotection of theimidazole would yield compounds of Formula (I).

Another variation of Scheme I is depicted in Scheme IV below.

Protected bromoimidazole (1d) or the corresponding unprotected imidazole(1e), from Scheme I, may be cross-coupled to the sulfonamide boronateester (4a) to furnish the corresponding substituted imidazole (4b) ordirectly to compounds of Formula (I).

A corollary to the route described in Scheme I in the synthesis ofcompounds of Formula (I) is summarized below in Scheme V.

Tribromoimidazole may be protected as described in Scheme I to produceintermediate (5a). Selective C-2 Suzuki cross-coupling with anoptionally substituted phenyl boronic acid or ester could provide thecommon intermediate (1a) which could then be elaborated to compounds ofFormula (I) as outlined in Scheme I. See Tetrahedron Letters, 1998, 39,5171.

Those of skill in the art will appreciate that compounds of the presentinvention could be made using procedures analogous to those described inthe Example section below.

The compounds of the present invention (including intermediates) may beisolated and used per se or in the form of its pharmaceuticallyacceptable salt, solvate and/or hydrate. Many of the intermediates andcompounds represented by Formula I are capable of forming acid additionsalts, particularly pharmaceutically acceptable acid addition salts.Pharmaceutically acceptable acid addition salts of the compound of thepresent invention include those of inorganic acids, for example,hydrohalic acids such as hydrochloric acid, hydrobromic acid orhydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; andorganic acids, for example aliphatic monocarboxylic acids such as formicacid, acetic acid, acid and butyric acid, aliphatic hydroxy acids suchas lactic acid, citric acid, tartaric acid or malic acid, dicarboxylicacids such as maleic acid or succinic acid, aromatic carboxylic acidssuch as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid ortriphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoicacid, p-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid or3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such asmethanesulfonic acid or benzenesulfonic acid. These salts may beprepared from compounds of Formula I or II by known salt-formingprocedures.

Compounds of the present invention which contain acidic, e.g. carboxyl,groups, are also capable of forming salts with bases, in particularpharmaceutically acceptable bases such as those well known in the art;suitable such salts include metal salts, particularly alkali metal oralkaline earth metal salts such as sodium, potassium, magnesium orcalcium salts, or salts with ammonia or pharmaceutically acceptableorganic amines or heterocyclic bases such as ethanolamines, benzylaminesor pyridine. These salts may be prepared from compounds of Formula I byknown salt-forming procedures.

For those compounds containing an asymmetric carbon atom, the compoundsexist in individual optically active isomeric forms or as mixturesthereof, e.g. as racemic or diastereomeric mixtures. Unless specifiedotherwise, the present invention embraces both individual opticallyactive R and S isomers as well as mixtures, e.g. racemic ordiastereomeric mixtures, thereof. In addition, the present inventionembraces all geometric and positional isomers. For example, if acompound of the present invention incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, are embracedwithin the scope of the invention.

Diastereomeric mixtures can be separated into their individualdiastereoisomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereoisomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a commerciallyavailable chiral High pressure liquid chromatography (HPLC) column.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. For purposes of the presentinvention, solvates (including hydrates) are considered pharmaceuticalcompositions, e.g., a compound of Formula I or II (or pharmaceuticallyacceptable salt thereof) in combination with an excipient, wherein theexcipient is a solvent. The compound per se, pharmaceutical saltthereof, or a solvate/hydrate of the compound or salt may exist ineither amorphous or crystalline form (e.g., polymorphs).

It is also possible that the intermediates and compounds of the presentinvention may exist in different tautomeric forms, and all such formsare embraced within the scope of the invention. The term “tautomer” or“tautomeric form” refers to structural isomers of different energieswhich are interconvertible via a low energy barrier. For example, protontautomers (also known as prototropic tautomers) include interconversionsvia migration of a proton, such as keto-enol and imine-enamineisomerizations. A specific example of a proton tautomer is the imidazolemoiety where the proton may migrate between the two ring nitrogens.Valence tautomers include interconversions by reorganization of some ofthe bonding electrons.

The present invention includes all pharmaceutically acceptableisotopically-labeled compounds of Formula (I) or (II) wherein one ormore atoms are replaced by atoms having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberusually found in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention comprises isotopes of hydrogen, such as ²H and ³H, carbon,such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Isotopically-labeled compounds of the present invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying Examplesand Preparations Sections using an appropriate isotopically-labeledreagent in place of the non-labeled reagent previously employed.

The compounds of the invention are useful in vitro and/or in vivo ininhibiting the growth of cancer cells. Consequently, the compounds ofthe present invention (including the compositions and processes usedtherein) may be used in the manufacture of a medicament for thetherapeutic applications described herein. The compounds may be usedalone or in compositions together with a pharmaceutically acceptablecarrier, solvents (including water), or excipient. Suitablepharmaceutically acceptable carriers, diluents, or excipients include,for example, processing agents and drug delivery modifiers andenhancers, such as, for example, calcium phosphate, magnesium stearate,talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrose,hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, low melting waxes,ion exchange resins, and the like, as well as combinations of any two ormore thereof. Other suitable pharmaceutically acceptable excipients aredescribed in “Remington's Pharmaceutical Sciences,” Mack Pub. Co., NewJersey (1991), incorporated herein by reference. The pharmaceuticalcompositions include the incorporation of solvents (including water)into a crystalline matrix of the compound (also referred to as solvatesand hydrates).

Compounds of the invention modulate the activity of kinases and, assuch, are useful for treating diseases or disorders in which kinases,contribute to the pathology and/or symptomology of the disease. Examplesof kinases that are inhibited by the compounds and compositionsdescribed herein and against which the methods described herein areuseful include, but are not limited to, B-Raf.

The Ras-Raf-MEK-ERK signaling pathway transmits signals from cellsurface receptors to nucleus and is essential for cell proliferation andsurvival. Since 10-20% of human cancers harbor oncogenic Ras mutationand many human cancers have activated growth factor receptors, thispathway is an ideal target for intervention.

The Raf family of serine/threonine kinase include three members: C-Raf(or Raf-1), B-Raf and A-Raf. Both the essential role and the position ofRaf in many signaling pathways have been demonstrated from studies usingderegulated and dominant inhibitory Raf mutants in mammalian cells aswell as from studies employing biochemical and genetic techniques tomodel organisms. In the past, the focus on Raf being an anti-tumor drugtarget centered on its function as a downstream effector of Ras.However, recent findings suggest that Raf may have a prominent role inthe formation of certain tumors with no requirement of an oncogenic Rasallele. In particular, activating alleles of B-Raf have been identifiedin ˜70% of melanomas, 40% of papillary thyroid carcinoma, 30% of ovarianlow-grade carcinoma, and 10% of colorectal cancers. Most B-Raf mutationsare found within the kinase domain, with a single substitution (V599E)accounting for 80%. The mutated B-Raf proteins activate Raf-MEK-ERKpathway either via elevated kinase activity toward MEK or via activatingC-Raf.

Therefore, development of a kinase inhibitor for B-Raf provides a newtherapeutic opportunity for treatment of many types of human cancers,especially for metastatic melanomas, solid tumors, brain tumors such asGlioblastoma multiform (GBM), acute myelogenous leukemia (AML),papillary thyroid carcinoma, ovarian low-grade carcinoma, and colorectalcancer. Several Raf kinase inhibitors have been described as exhibitingefficacy in inhibiting tumor cell proliferation in vitro and/or in vivoassays (see, for example, U.S. Pat. Nos. 6,391,636; 6,358,932;6,037,136; 5,717,100; 6,458,813; 6,204,467; and 6,268,391). Otherpatents and patent applications suggest the use of Raf kinase inhibitorsfor treating leukemia (see, for example, U.S. Pat. Nos. 6,268,391;6,204,467; 6,756,410; and 6,281,193; and abandoned U.S. PatentApplication Nos. 20020137774 and 20010006975), or for treating breastcancer (see, for example, U.S. Pat. Nos. 6,358,932; 5,717,100;6,458,813; 6,268,391; 6,204,467; and 6,911,446).

The compounds of the present invention inhibit cellular processesinvolving B-Raf kinase by blocking the signal cascade in these cancercells and ultimately inducing stasis and/or death of the cells.

In accordance with the foregoing, the present invention further providesa method for preventing or treating any of the diseases or disordersdescribed above in a subject in need of such treatment, which methodcomprises administering to said subject a therapeutically effectiveamount (See, “Administration and Pharmaceutical Compositions”, infra) ofa compound of Formula I or a pharmaceutically acceptable salt thereof.For any of the above uses, the required dosage will vary depending onthe mode of administration, the particular condition to be treated andthe effect desired.

In general, compounds of the invention will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Ingeneral, satisfactory results are indicated to be obtained systemicallyat daily dosages of from about 0.03 to 2.5 mg/kg per body weight. Anindicated daily dosage in the larger mammal, e.g. humans, is in therange from about 0.5 mg to about 100 mg, conveniently administered, e.g.in divided doses up to four times a day or in retard form. Suitable unitdosage forms for oral administration comprise from ca. 1 to 50 mg activeingredient.

The pharmaceutical formulations may be prepared using conventionaldissolution and mixing procedures. For example, the bulk drug substance(i.e., compound of the present invention or stabilized form of thecompound (e.g., complex with a cyclodextrin derivative or other knowncomplexation agent)) is dissolved in a suitable solvent in the presenceof one or more of the excipients described above. The compound of thepresent invention is typically formulated into pharmaceutical dosageforms to provide an easily controllable dosage of the drug and to givethe patient an elegant and easily handleable product.

Compounds of the invention can be administered as pharmaceuticalcompositions by any conventional route, in particular enterally, e.g.,orally, e.g., in the form of tablets or capsules, or parenterally, e.g.,in the form of injectable solutions or suspensions, topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form. Pharmaceutical compositions comprising a compound ofthe present invention in free form or in a pharmaceutically acceptablesalt form in association with at least one pharmaceutically acceptablecarrier or diluent can be manufactured in a conventional manner bymixing, granulating or coating methods. For example, oral compositionscan be tablets or gelatin capsules comprising the active ingredienttogether with a) diluents, e.g., lactose, dextrose, sucrose, mannitol,sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum,stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;for tablets also c) binders, e.g., magnesium aluminum silicate, starchpaste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and or polyvinylpyrrolidone; if desired d)disintegrants, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and/or e) absorbents, colorants, flavors andsweeteners. Oral formulations can also comprise the active ingredientalong with 20-60% Eudragit EPO, Hydroxypropyl cellulose EF,Hydroxypropyl methylcellulose, or Kollidon VA64, and up to 5% ofpluronic F68, Cremophor EL, or Gelucire 44/14. Injectable compositionscan be aqueous isotonic solutions or suspensions, and suppositories canbe prepared from fatty emulsions or suspensions. The compositions may besterilized and/or contain adjuvants, such as preserving, stabilizing,wetting or emulsifying agents, solution promoters, salts for regulatingthe osmotic pressure and/or buffers. In addition, they may also containother therapeutically valuable substances. Suitable formulations fortransdermal applications include an effective amount of a compound ofthe present invention with a carrier. A carrier can include absorbablepharmacologically acceptable solvents to assist passage through the skinof the host. For example, transdermal devices are in the form of abandage comprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound to the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin. Matrix transdermal formulations may also beused. Suitable formulations for topical application, e.g., to the skinand eyes, are preferably aqueous solutions, ointments, creams or gelswell-known in the art. Such may contain solubilizers, stabilizers,tonicity enhancing agents, buffers and preservatives.

In some therapies, it may be advantageous to administer the compounds ofthe invention in combination with one or more therapeutic agents(pharmaceutical combinations). For example, synergistic effects canoccur with other anti-tumor or anti-proliferative agents, for example,mitotic inhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors (e.g., trastuzumab, panitumumab,cetuximab, gefitinib, erlotinib, lapatinib, sorafenib, etc.), cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, antibodies, cytotoxics, anti-hormones, anti-androgens, ananti-angiogenesis agent, kinase inhibitor, pan kinase inhibitor orgrowth factor inhibitor. Suitable therapeutic agents include erlotinib,docetaxel, gemcitabine, cisplatin, carboplatin, paclitaxel, bevacizumab,trastuzumab, pertuzumab, temozolomide, taxoxifen, doxorubicin, rapamycinand lapatnib. Other suitable therapeutic agents are listed in thePhysicians Desk Reference.

Preferred therapeutic agents for combination therapy include MEKinhibitors (e.g., sorafenib, AZD6244 (Example 10 of WO 03/077914),2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide,4-(4-bromo-2-fluorophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxamide,PD-0325901(N-[(2-R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamideavailable from Axon Medchem), PD-184352(2-(2-chloro-4-iodophenyl)amino-N-(cyclopropylmethoxy)-3,4-difluorobenzamideavailable from Axon Medchem), PD-0325901(N—[((R)-2,3-dihydroxypropyl)oxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamideavailable from Axon Medchem), SL-327(α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrileavailable from Axon Medchem), XL-518 (Exelixis), AR-119 (ArdeaBiosciences, Valeant Pharmaceuticls), AS-701173 (Merck Serono),AS-701255 (Merck Serono), 360770-54-3 (Wyeth), RDEA119((S)—N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide)):

mTOR inhibitors (e.g., Rapamycin (sirolimus), TORISEL™ (temsirolimus),RAD001 (everolimus), AP23573 (deforolimus), OSI-027 (OSIPharmaceuticals), compounds described in WO 06/090167; WO 06/090169; WO07/080382, WO 07/060404; and WO08/023161): and

PI3K inhibitors (e.g., wortmannin, 17-hydroxywortmannin analogsdescribed in WO 06/044453,4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno-[3,2-d]pyrimidin-4-yl)morpholine,(S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one,4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno-[2,3-d]pyrimidin-4-yl)morpholine,LY294002 (2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one availablefrom Axon Medchem), PI 103 hydrochloride(3-[4-(4-Morpholinylpyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl]phenolhydrochloride available from Axon Medchem), PIK 75(N′-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfono-hydrazidehydrochloride available from Axon Medchem), PIK 90(N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamideavailable from Axon Medchem), GDC-0941 bismesylate(-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidinebismesylate available from Axon Medchem), BEZ235(2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrileavailable from Axon Medchem), AS-252424(5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dioneavailable from Axon Medchem), and TGX-221(7-Methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-oneavailable from Axon Medchem), XL-765, and XL-147.

Where the compounds of the invention are administered in conjunctionwith other therapies, dosages of the co-administered compounds will ofcourse vary depending on the type of co-drug employed, on the specificdrug employed, on the condition being treated and so forth.

According to the methods of the invention, a compound of the presentinvention or a combination of a compound of the present invention and atleast one additional pharmaceutical agent is administered to a subjectin need of such treatment, preferably in the form of a pharmaceuticalcomposition. In the combination aspect of the invention, the compound ofthe present invention and at least one other pharmaceutical agent(described above) may be administered either separately or in thepharmaceutical composition comprising both. It is generally preferredthat such administration be oral. However, if the subject being treatedis unable to swallow, or oral administration is otherwise impaired orundesirable, parenteral or transdermal administration may beappropriate.

According to the methods of the invention, when a combination of acompound of the present invention and at least one other pharmaceuticalagent are administered together, such administration can be sequentialin time or simultaneous with the simultaneous method being generallypreferred. For sequential administration, a compound of the presentinvention and the additional pharmaceutical agent can be administered inany order. It is generally preferred that such administration be oral.It is especially preferred that such administration be oral andsimultaneous. When a compound of the present invention and theadditional pharmaceutical agent are administered sequentially, theadministration of each can be by the same or by different methods.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well-known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings. Theinvention also provides for a pharmaceutical combinations, e.g. a kit,comprising a) a first agent which is a compound of the invention asdisclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one additional therapeutic agent. The kit cancomprise instructions for its administration.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the 2compounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of 3 or more activeingredients.

EXAMPLES

The present invention is further exemplified, but not limited, by thefollowing intermediates and examples that illustrate the preparation ofcompounds of the present invention.

Preparative separations are carried out using a CombiFlash® Rf system(Teledyne Isco Inc. Lincoln, Nebr.) in combination with RediSep®Normal-Phase Silica Flash Columns (4 g-120 g, 35-70 micron particlesize; Teledyne Isco Inc.), or by flash column chromatography usingsilica gel (230-400 mesh) packing material, or by HPLC using a WATERS2767 Sample Manager, C-18 reversed phase column, 30×50 mm, flow 75mL/min. Typical solvents employed for the CombiFlash® system and flashcolumn chromatography are dichloromethane, methanol, ethyl acetate,hexane, acetone, aqueous ammonia (or ammonium hydroxide), and triethylamine Typical solvents employed for the reverse phase HPLC are varyingconcentrations of acetonitrile and water with 0.1% trifluoroacetic acid(TFA).

Microwave reactions conducted in a Creator or Initiator microwave system(Biotage, Charlottesville, Va.)

The following acronyms having the corresponding meanings are used in theexperimental section below.

DEAD—diethyl azodicarboxylate DIEA—diisopropylethyl amineTHF—tetrahydrofuran Et₂O—diethyl ether DMF—dimethylformamideNMP—N-methylpyrrolidinone DME—1,1-dimethoxyethane DPPA—diphenylphosphorazide EtOAc—ethyl acetate TFA—trifluoroacetic acidNBS—N-bromosuccinimide dba—dibenzylideneacetonedppf—bis(diphenylphosphino)ferrocene PPTS—pyridinium p-toluenesulfonate

Preparation of Key Starting Materials and Intermediates Preparation ofstarting material (S)-tert-butyl 1-aminopropan-2-ylcarbamate (SM-1)

Step 1. Preparation of (S)-tert-butyl1-(1,3-dioxisoindolin-2-yl)propan-2-ylcarbamate

To a stirred solution of (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate(7.4 g, 42.2 mmol) in dry THF (420 mL) were added phthalimide (6.83 g,46.4 mmol) and PPh₃ (12.18 g, 46.4 mmol) DEAD (7.3 mL, 46.4 mmol) wasthen added dropwise to the stirred solution at room temperature, andmaintained for 3 hours. The reaction mixture was then concentrated andthe resulting residue was purified by flash chromatography (SiO₂, 30-70%EtOAc in hexanes) to provide 12.5 g of (S)-tert-butyl1-(1,3-dioxisoindolin-2-yl)propan-2-ylcarbamate. LCMS (m/z) 205.1(MH⁺-BOC), t_(R)=0.86 minute; ¹H NMR (CDCl₃, 400 MHz) δ 7.82-7.87 (m,2H), 7.67-7.75 (m, 2H), 4.60-4.76 (br d, 1H), 4.03-4.20 (br s, 1H),3.62-3.72 (m, 2H), 1.25 (s, 9H), 1.21 (d, J=6.6 Hz, 3H).

Step 2. Preparation of (S)-tert-butyl 1-aminopropan-2-ylcarbamate (SM-1)

Hydrazine monohydrate (20 mL, 642.7 mmol) was added to a suspension of(S)-tert-butyl 1-(1,3-dioxisoindolin-2-yl)propan-2-ylcarbamate (12.5 g,41.1 mmol) in dry methanol (150 mL), and the resulting mixture washeated to 50° C. for 1 hour. After cooling to room temperature, thereaction mixture was filtered through a sintered funnel, and thefiltrate concentrated. The resulting residue was suspended in diethylether (300 mL) and filtered, washing the filter cake thoroughly withdiethyl ether. The combine filtrates were filtered and concentrated tofurnish 6.3 g of (S)-tert-butyl-1-aminopropan-2-ylcarbamate: ¹H NMR(CDCl₃, 400 MHz) δ 4.44-4.71 (br s, 1H), 3.53-3.74 (br m, 1H), 2.75 (dd,J=4.9, 12.9 Hz, 1H), 2.64 (dd, J=6.6, 12.9 Hz, 1H), 1.45 (s, 9H),1.15-1.34 (br s, 2H), 1.12 (d, J=6.7 Hz, 3H).

Preparation of starting material (S)-tert-butyl1-aminopropan-2-ylcarbamate (SM-2)

(R)-tert-butyl 1-aminopropan-2-ylcarbamate was prepared in a similarfashion as above using (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate asthe starting material.

Preparation of starting material 3-amino-2-methylpropanenitrile (SM-3)

Following the procedure described in U.S. Pat. No. 2,659,739, a 200 mLsteel bomb was charged with 32% aqueous ammonia solution (81 mL) and ofmethacrylonitrile (18 g, 23 mL, 270 mmol). The reaction vessel wassealed and heated to 135° C. with stirring for 2 hours. The reaction wasallowed to cool to room temperature and the reaction mixture wasdistilled under reduced pressure (84-85° C., 24 mbar) to furnish 12.4 g(147 mmol, 53%) 3-amino-2-methylpropanenitrile as a colorless oil: ¹HNMR (CDCl₃, 400 MHz) δ 2.89 (dd, J=4.9, 6.5 Hz, 2H), 2.63-2.72 (m, 1H),1.37 (2H), 1.32 (m, 2H), 1.31 (d, J=7.4 Hz, 3H).

Preparation of starting material 3-amino-2-methylpropanenitrile (SM-4)

Step 1. Preparation of 1-(hydroxymethyl)cyclopropanecarbonitrile

Following a procedure reported in WO 2009/024550, a solution of ethyl1-cyanocyclopropanecarboxylate (4.0 g, 28.7 mmol) in a DME (80 mL) andmethanol (8 mL) was treated with NaBH₄ (8.7 g, 230 mmol) and stirred atroom temperature for 24 hours. The reaction was then quenched withsaturated aqueous NaHCO₃ solution (100 ml) with gas evolution undercontrol, and then extracted with 9:1 DCM-MeOH (3×50 ml). The organiclayers were combined, dried (Na₂SO₄), concentrated to give1-(hydroxy-methyl)-cyclopropanecarbonitrile (2.34 g, 24.1 mmol, 84%) asa colorless oil which was used without further purification: ¹H NMR (300MHz, CDCl₃) δ 3.63 (s, 2H), 2.10-2.45 (br s, 1H), 1.20-1.35 (m, 2H),0.90-1.05 (m, 2H).

Step 2. Preparation of 1-((1,3-dioxoisoindolin-2yl)methyl)cyclopropanecarbonitrile

A solution of 1-(hydroxymethyl)-cyclopropanecarbonitrile (5.52 g, 56.8mmol), phthalimide (9.20 g, 62.5 mmol), and triphenylphosphine (16.4 g,62.5 mmol) in THF (550 mL) was treated with DEAD (9.90 mL, 62.5 mmol)and stirred at room temperature for 17 hours. The reaction mixture wasthen concentrated and the resulting solids were triturated in diethylether (150 mL), and collected by filtration. Purification by flashchromatography (SiO₂, 0-20% EtOAc in DCM) afforded1-((1,3-dioxoisoindolin-2-yl)methyl)-cyclopropanecarbonitrile (8.8 g,38.8 mmol, 68%) as a white solid: LCMS (m/z) 227.0 (MH⁺), t_(R)=0.66minute; ¹H NMR (300 MHz, CDCl₃) δ 7.90 (dd, J=5.4, 3.1 Hz, 2H), 7.77(dd, J=5.4, 3.1 Hz, 2H), 3.81 (s, 2H), 1.30-1.44 (m, 2H), 1.28 (d, J=3.8Hz, 2H).

Step 3. Preparation of 1-(aminomethyl)cyclopropanecarbonitrile (SM-4)

A solution of1-((1,3-dioxoisoindolin-2-yl)methyl)cyclopropanecarbonitrile (8.78 g,38.8 mmol), hydrazine monohydrate (9.5 ml, 190 mmol) in MeOH (150 mL)was heated at 60° C. for 3 h with precipitation occurring 30 min afterheating. The reaction mixture was then cooled down to room temperatureand filtered. The filtrate was concentrated in vacuo and the resultingresidue was sonicated with Et₂O (150 mL). The resulting suspension wasfiltered through a sintered funnel, and the filtrate was concentratedand dried in vacuo to provide 1-(aminomethyl)-cyclopropanecarbonitrile(3.6 g, 36.3 mmol, 93%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ2.76 (s, 2H), 1.60-2.25 (br s, 2H), 1.16-1.35 (m, 2H), 0.79-0.98 (m,2H).

Preparation of starting material5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-5)

Step 1: Preparation of 3-bromo-5-chloro-2-fluorobenzoic acid

To a cooled solution of diisopropylamine (2.4 mL, 17.2 mmol) in dry THF(15 mL) under Argon at 0° C. was added n-butyllithium (7.5 mL, 2.0 M inpentane, 15.0 mmol). After 30 minutes the solution was cooled to −78° C.and a solution of 2-bromo-4-chloro-1-fluorobenzene (3 g, 14.3 mmol) indry THF (15 mL) was added over 15 minutes. After 1 hour, this solutionwas transferred via cannula over 10 minutes to a mixture of solid carbondioxide and THF (30 mL) at −78° C. After 45 minutes the cold bath wasremoved and excess carbon dioxide was allowed to vent while the solutionwarmed to room temperature. The reaction mixture was then quenched withaqueous 0.5 M HCl solution (60 mL). After concentrating, the remainingaqueous phase was basified with aqueous 0.5 M NaOH solution and waswashed with ethyl acetate (100 mL). The aqueous phase was then acidifiedwith aqueous 1.0 M HCl solution and extracted with chloroform (2×75 mL).The combined organic portions were washed with brine, dried (Na₂SO₄) andconcentrated to give 3.34 g of a semi-crystalline solid as a mixture ofregioisomers with the desired isomer as the major: LCMS (m/z) notobserved (MH⁺), t_(R)=0.66 minute; ¹H NMR (400 MHz, CDCl₃) δ 7.80 (dd,J=5.5, 2.7 Hz, 1H), 7.95 (dd, J=5.5, 2.7 Hz, 1H).

Step 2: Preparation of tert-butyl3-bromo-5-chloro-2-fluorophenyl-carbamate

A mixture of 3-bromo-5-chloro-2-fluorobenzoic acid (3.34 g, 13.2 mmol),DIEA (2.04 g, 15.8 mmol) and diphenyl phosphorazide (DPPA, 4.53 g, 16.5mmol) in 1:1 dry t-butanol and toluene (35 mL) was heated to andmaintained at reflux for 23 hours. The reaction was allowed to cool toroom temperature and was then partitioned between CHCl₃ (75 mL) andwater (75 mL). The organic layer was separated, washed with brine, dried(Na₂SO₄), and then concentrated under reduced pressure to yield an oilyresidue. Purification by flash chromatography (SiO₂, 0-5% EtOAc inheptane) to yield tert-butyl 3-bromo-5-chloro-2-fluorophenylcarbamate(2.45 g, 7.5 mmol, 57%): LCMS (m/z) not ionized (MH⁺), t_(R)=1.20minutes; ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J=5.1 Hz, 1H), 7.16 (m, 1H),6.72 (br s, 1H), 1.53 (s, 9H).

Step 3. Preparation of 3-bromo-5-chloro-2-fluoroaniline

tert-Butyl 3-bromo-5-chloro-2-fluorophenylcarbamate (1.0 g, 3.1 mmol)was treated with 4.0 M HCl in dioxane (10 mL) and the resulting reactionwas maintained at room temperature for 4 hours. The reaction mixture wasconcentrated and partitioned between EtOAc (200 mL) and saturatedaqueous NaHCO₃ solution (75 mL). The layers were separated and theorganic portion was washed with brine (75 mL), dried (Na₂SO₄), andconcentrated to give 3-bromo-5-chloro-2-fluoroaniline as a colorless oilwhich was carried forward without further purification: LCMS (m/z) 225.9(MH⁺), t_(R)=0.96 minute; ¹H NMR (400 MHz, CDCl₃) δ 6.88 (m, 1H), 6.70(d, J=7.0 Hz, 1H).

Step 4. Preparation of5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-5)

A mixture of 3-bromo-5-chloro-2-fluoroaniline (0.69 g, 3.1 mmol),bis(pinacolato)diboron (0.94 g, 3.7 mmol), and potassium acetate (0.91g, 9.2 mmol) in dry dioxane (11 mL) was sparged with N₂. Dichloro1,1′-bis(diphenylphosphino)ferrocene palladium (0.23 g, 0.31 mmol) wasthen added and the reaction vial sealed. The mixture was heated with anoil bath at 105° C. for 3.5 hours. The reaction mixture was then allowedto cool to room temperature, centrifuged, and the supernatant, whichcontained the desired compound5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline,was decanted and used without further purification: LCMS (m/z) 189.9(MH⁺, boronic acid), t_(R)=0.43 minute.

Preparation ofN-(5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(SM-6)

Step 1. Preparation ofN-(3-bromo-5-chloro-2-fluorophenyl)propane-1-sulfonamide

To a solution of 3-bromo-5-chloro-2-fluoroaniline (SM-5, step 3, 0.52 g,2.3 mmol) in pyridine (2.5 mL) cooled in an ice water bath was addedpropane-1-sulfonyl chloride (0.3 mL, 2.8 mmol). After 4 hours thesolution was concentrated and partitioned between EtOAc (75 mL) andaqueous 0.1 M HCl solution (30 mL). The layers were separated and theorganic phase was then washed with brine, dried (Na₂SO₄) andconcentrated to give 778 mg ofN-(3-bromo-5-chloro-2-fluorophenyl)propane-1-sulfonamide as a yellowsolid which was carried forward without further purification: LCMS (m/z)not observed, t_(R)=0.95 minute.

Step 2. Preparation ofN-(5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(SM-6)

This material was prepared following the procedure used for SM-5, step4: LCMS (m/z) 590.3 (2×MH⁺), t_(R)=0.67 minute.

Preparation of starting2,5-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-7)

Step 1. Preparation of 3-bromo-2,5-difluoroaniline

A mixture of 1,3-dibromo-2,5-difluorobenzene (4 g, 14.7 mmol),benzophenone imine (2.6 mL, 15.5 mmol), sodium tert-butoxide (2.1 g,22.1 mmol), (S)-BINAP (1.4 g, 2.2 mmol), in toluene (15 mL) was spargedwith Argon and charged with Pd₂(dba)₃ (0.67 g, 0.74 mmol). The reactionwas then sealed and irradiated at 100° C. for 30 minutes in a microwavereactor. The reaction mixture was diluted with Et₂O and stirred for 2hours with a palladium scavenger (Siliabond DMT). The mixture wasfiltered through a plug of Celite and the collected filtrate waspartitioned between diethyl ether and water, and the resulting layersseparated. The organic portion was washed with water, brine, dried(MgSO₄), and concentrated to afford a brown red solid. The solid wasdissolved in THF (40 mL) and treated with aqueous 6.0 N HCl solution (25ml, 150 mmol). The reaction was stirred for 1.5 hours at roomtemperature was partitioned between water and Et₂O. The layers wereseparated and the aqueous portion was brought to a pH of 9 with aqueous1.0 M NaOH solution. The basic aqueous layer was extracted diethyl ether(3×30 mL) the combined diethyl ether layers were washed with aqueous 1.0M NaOH solution, water, brine, dried (MgSO₄), concentrated. Purificationby flash chromatography (SiO₂, 0-10% EtOAc in heptane) afforded3-bromo-2,5-difluoroaniline (1.7 g, 8.2 mmol, 56%, trace benzophenone)as an orange solid: ¹H NMR (400 MHz, CDCl₃) δ 3.93 (br s, 2H) 6.43 (m,1H) 6.62 (m, 1H).

Step 2. Preparation of2,5-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

To a solution of 3-bromo-2,5-difluoroaniline (2.0 g, 9.4 mmol),bis(pinacolato)diboron (2.86 g, 11.25 mmol), tricyclohexylphosphine(0.184 g, 0.656 mmol), and potassium acetate (1.380 g, 14.06 mmol) in1,4 dioxane (1.0 ml), was added Pd₂(dba)₃ (0.26 g, 0.28 mmol) and theresulting reaction mixture was irradiated to 120° C. in the microwavefor 30 minutes. The reaction was allowed to cool to room temperature andwas diluted with EtOAc and the reaction was diluted with EtOAc andpalladium scavenger (Silicycle DMT) was added and mixture was stirredfor 30 minutes, then filtered through a sintered funnel. The filtratewas washed with water, brine, dried (MgSO4), and concentrated to affordfiltered and stripped to2,5-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.4g, 9.4 mmol): LCMS (m/z) 255.1 (MH⁺), t_(R)=0.95 minute; LCMS (m/z)174.0 (MH⁺, boronic acid), t_(R)=0.3 minute.

Preparation of starting material2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-8)

Step 1. Preparation of 3-bromo-2-chloro-5-fluoroaniline

To a sealable glass tube was charged1,3-dibromo-2-chloro-5-fluorobenzene (12.52 g, 43.4 mmol), benzophenoneimine (8.26 g, 45.6 mmol), sodium tert-butoxide (6.26 g, 65.1 mmol), andtoluene (100 mL). The resulting mixture was thoroughly sparged withArgon, followed by the addition of Pd₂(dba)₃ (0.398 g, 0.434 mmol) and(S)-BINAP (0.81 g, 1.3 mmol), and follow by another Argon sparge. Thereaction tube was sealed and heated to 85° C. in an oil bath andmaintained overnight. The reaction was allowed to cool to roomtemperature and quenched with water (20 mL). The resulting layers werepartitioned and separated. The organic phase was concentrated andassayed to be a mixture of mono- and bis-aminated products (˜4:1 by HPLCarea at 220 nm). The residue was dissolved in THF (70 mL), treated withaqueous 3.0 M HCl (20 mL) at room temperature for 1 hour and basifiedwith saturated aqueous Na₂CO₃ solution (40 mL). The reaction mixture wasallowed to partition and the layers were separated. The organic portionwas separated, washed with brine, concentrated and the resulting residuewas purified by flash chromatography (SiO₂, 0-15% EtOAc in heptane) and3-bromo-2-chloro-5-fluoroaniline was obtained as a light yellow solid(6.82 g, 30.4 mmol): LCMS (m/z): not ionized (MH⁺), t_(R)=0.95 minute;¹H NMR (CDCl₃, 300 MHz) δ 4.32 (br s, 2H), 6.44 (dd, J=9.8, 2.8 Hz, 1H),6.77 (dd, J=7.9, 2.6 Hz, 1H).

Step 2. Preparation of2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-8)

To a glass pressure vial was added 3-bromo-2-chloro-5-fluoroaniline(10.22 g, 45.5 mmol), bis(pinacolato)diboron (13.9 g, 54.6 mmol),tricyclohexylphosphine (0.89 g, 3.2 mmol), potassium acetate (6.70 g,68.3 mmol), and Pd(dba)₂ (1.31 g, 2.3 mmol) in 1,4-dioxane (170 mL) togive a red suspension which was sparged with nitrogen, and the reactionvessel was then sealed. The reaction mixture was heated in an oil bathto 120° C. for 5 hours and was then allowed to cool to room temperature.SiliaBond DMT (10 g, from Silicycle) was added and mixture stirred 1hour at room temperature. The mixture was diluted with EtOAc andfiltered through neutral alumina with a cover of silica gel, washing thefilter cake thoroughly with EtOAc. The combined filtrates werepartitioned with water and the phases separated. The aqueous phase wasextracted with EtOAc. The organic phases were combined, washed withwater, brine, dried (Na₂SO₄), filtered and concentrated to a yellow oil.Heptane was added and mixture briefly sonicated to provide a suspensionwhich upon concentration afforded2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(14.64 g, 35.0 mmol, 65% purity by ¹H NMR) as an orange solid which wasused without further purification. A purified sample (SiO₂, 0-50% EtOAcin heptane) was obtained for characterization: LCMS (m/z): 272.0 (MH⁺),t_(R)=0.99 minute: ¹H NMR (300 MHz, CDCl₃) δ 1.36 (s, 12H) 4.17 (br s,2H) 6.53 (dd, J=9.8, 2.7 Hz, 1H) 6.76 (dd, J=8.6, 2.7 Hz, 1H).

Preparation of Starting material2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (SM-9)

Step 1. Preparation of 1-bromo-2-chloro-3-nitrobenzene

To an oven dried round-bottom flask fitted with stir bar and an ovendried condenser under N₂ at room temperature was added2-chloro-3-nitrobenzoic acid (6.0 g, 29.8 mmol), mercuric oxide, red(9.67 g, 44.7 mmol) and carbon tetrachloride (200 mL). The reactionmixture heated to 90° C. for 30 minutes with irradiation from a 150 WTYPE A utility light bulb. The reaction mixture was then cooled toapproximately 60° C. and bromine (2.30 mL, 44.7 mmol) added dropwise viasyringe and the nitrogen inlet was replaced with an Ar balloon. Thereaction mixture was heated again to 90° C. for 4 hours under constantirradiation from the light bulb. The reaction was allowed to cool toroom temperature, quenched with saturated aqueous NaHCO₃ solution andDCM and stirred for 30 minutes. The phases partitioned upon standing andthen were separated. The aqueous portion was extracted with DCM. Thecombined organic phases were washed with water, brine, dried (Na₂SO₄),filtered and concentrated in vacuo to afford 7.04 g of1-bromo-2-chloro-3-nitrobenzene: ¹H NMR (400 MHz, CDCl₃) δ 7.31 (t,J=8.0 Hz, 1H) 7.74 (dd, J=8.2, 1.2 Hz, 1H) 7.87 (dd, J=8.0, 1.4 Hz, 1H).

Step 2. Preparation of 3-bromo-2-chloroaniline

To a solution of 1-bromo-2-chloro-3-nitrobenzene (3.0 g, 12.7 mmol) inMeOH (127 ml) was added Zn dust (8.30 g, 127 mmol) followed by NH₄Cl(6.79 g, 127 mmol) which resulted in a significant exotherm. Theheterogeneous reaction mixture was stirred at room temperature for 1hour. The reaction mixture was filtered through a pad of Celite andconcentrated to an off-white solid. To this solid was added EtOAc andthe resulting mixture was sonicated for 10 minutes. The mixture wasfiltered through Celite and washed with EtOAc. The combine filtrateswere concentrated in vacuo to afford 2.17 g (10.5 mmol, 79%) of3-bromo-2-chloroaniline: LCMS (m/z): 205.9 (MH⁺); t_(R)=0.87 minute: ¹HNMR (400 MHz, CDCl₃) δ 6.62-6.66 (m, 1H) 6.87 (t, J=8.0 Hz, 1H) 6.97 (d,J=7.8 Hz, 1H) 7.22 (d, J=9.0 Hz, 1H).

Step 3. Preparation2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (SM-9)

To a glass pressure vessel was added 3-bromo-2-chloroaniline (3.08 g,14.9 mmol), bis(pinacolato)diboron (4.55 g, 17.9 mmol),tricyclohexylphosphine (0.29 g, 1.04 mmol), potassium acetate (2.2 g,22.4 mmol), and Pd₂dba₃ (0.41 g, 0.45 mmol) in 1,4-dioxane (75 mL) togive a red suspension which was sparged with nitrogen, and the reactionvessel was then sealed. The reaction was heated in an oil bath to 120°C. for 2 hours. LCMS of an aliquot indicted complete conversion and thereaction was allowed to cool to room temperature. SiliaBond DMT (4 gfrom SiliCycle) was added and the resulting mixture was stirred at roomtemperature for 30 minutes, then filtered through a plug of neutralalumina layered with SiO₂. The filter cake was washed thoroughly withEtOAc and the combined filtrates were partitioned water. The phases wereseparated and the aqueous portion was extracted with EtOAc. The combinedorganic portions were washed with water (2×), brine, dried (Na₂SO₄), andconcentrated to provide2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.6 g)as a dark yellow crystalline solid which was used without furtherpurification: LCMS (m/z) 254.0 (MH⁺); t_(R)=0.91 minute.

Preparation of starting materialN-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(SM-10)

Step 1. Preparation of N-(3-bromo-2-chlorophenyl) propane-1-sulfonamide

This material was prepared from 3-bromo-2-chloro aniline (SM-9, step 2)following the procedure used for SM-6, step 1. Purification by flashchromatography (SiO₂; 0-60% EtOAc in heptane) affordedN-(3-bromo-2-chlorophenyl)propane-1-sulfonamide (51%): ¹H NMR (400 MHz,CDCl₃) δ 1.05 (t, J=7.4 Hz, 3H) 1.83-1.95 (m, 2H) 3.01-3.15 (m, 2H) 4.21(br s, 1H) 7.17 (t, J=8.22 Hz, 1H) 7.44 (d, J=8.2 Hz, 1H) 7.67 (d,J=8.22 Hz, 1H).

Step 2. Preparation ofN-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(SM-10)

This material was prepared using the product from the previous step andfollowing the procedure used for SM-9, step 3 (88%): LCMS (m/z): 360.1(MH⁺); t_(R)=1.06 minutes.

Preparation of2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (SM-11)

Step 1. Preparation of 3-bromo-2-fluoroaniline

This material was prepared from 1-bromo-2-fluoro-3-nitrobenzene,following the procedure used for SM-9, step 2 (94%): LCMS (m/z) 189.9,t_(R)=0.74 minute; ¹H NMR (300 MHz, CDCl₃) δ 3.81 (br s, 2H) 6.64-6.75(m, 1H) 6.80 (t, J=8.2 Hz, 1H) 6.84-6.95 (m, 1H).

Step 2. Preparation of2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (SM-11)

This material was prepared following the procedure used for SM-9, step3: LCMS (m/z): 115.9 (MH⁺, boronic acid); t_(R)=0.17 minute.

Preparation of starting materialN-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(SM-12)

Step 1: Preparation of N-(3-bromo-2-fluorophenyl)propane-1-sulfonamide

This material was prepared from 3-bromo-2-fluoroaniline (SM-11, step 1),following the procedure used for SM-6, step 1. Purification by flashchromatography (SiO₂, 0-50% EtOAc in heptane) affordedN-(3-bromo-2-fluorophenyl) propane-1-sulfonamide (56%) as a whitecrystalline solid: ¹H NMR (400 MHz, CDCl₃) δ 1.05 (t, J=7.4 Hz, 3H)1.80-1.97 (m, 2H) 2.99-3.20 (m, 2H) 6.60 (br s, 1H) 7.04 (t, J=7.6 Hz,1H) 7.34 (app t, J=6.7 Hz, 1H) 7.56 (app t, J=7.6 Hz, 1H).

Step 2. Preparation ofN-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(SM-12)

This material was prepared following the procedure used for SM-9, step3, and was used in next steps without further characterization andpurification.

Preparation of starting material3,3,3-trifluoro-N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(SM-13)

Step 1. Preparation ofN-(3-bromo-2-fluorophenyl)-3,3,3-trifluoropropane-1-sulfonamide

This material was prepared from 3-bromo-2-fluoroaniline (SM-11, step 1),according to the procedure used for SM-6, step 1: LCMS (m/z) not ionized(MH⁺), t_(R)=0.92 minute; ¹H NMR (400 MHz, CDCl₃) δ ppm 2.62-2.82 (m,2H) 3.30-3.43 (m, 2H) 7.05-7.13 (m, 1H) 7.43 (t, J=6.9 Hz, 1H) 7.50-7.56(m, 1H).

Step 2. Preparation of3,3,3-trifluoro-N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(SM-13)

This material was prepared according to the procedure used for SM-9,step 3: LCMS (m/z) not ionized (MH⁺), t_(R)=0.62 minute.

Preparation ofN-(2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(SM-14)

Step 1. Preparation of bromo-2,6-difluorobenzoic acid

To an oven dried 2-necked round bottom flask under Argon at roomtemperature was added diisopropylamine (8.1 mL, 57.0 mmol) and THF (260mL). The solution was cooled to −70° C. in a dry ice-acetone bath.n-Butyllithium (2.0 M in cyclohexane, 25.9 mL, 51.8 mmol) was addedindropwise via syringe and the resulting reaction was warmed to 0° C.briefly then cooled back to −70° C. To this cold solution was added1-bromo-2,4-difluorobenzene (5.9 mL, 52.0 mmol) dropwise via syringe.After addition, the reaction was maintained at −70° C. for 1 hour.Carbon dioxide (5-9 g pieces, previously rinsed with dry THF) were addedto the solution. The Ar balloon was removed and replaced with a bubblerto allow venting. The resulting reaction was then allowed to warm toroom temperature and was quenched with a saturated aqueous NH₄Clsolution to pH-7-8. The aqueous mixture was washed with EtOAc, acidifiedwith aqueous 6 N HCl solution to pH-2-3, and extracted with EtOAc. Theorganic extract was washed with brine, dried (Na₂SO₄), filtered andconcentrated in vacuo to afford 10.9 g (89%) of3-bromo-2,6-difluorobenzoic acid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.25 (m,1H) 7.92 (m, 1H).

Step 2. Preparation of tert-butyl 3-bromo-2,6-difluorophenylcarbamate

To a round bottom flask containing 3-bromo-2,6-difluorobenzoic acid (5g, 21.1 mmol) under nitrogen with a condenser was added toluene (35 mL)and t-BuOH (35 mL). To this solution was added DIEA (4.4 ml, 25.3 mmol)and DPPA (5.7 mL, 26.4 mmol). The reaction mixture was heated to 111° C.in an oil bath for 48 hours. The reaction was allowed to cool to roomtemperature and the volatiles were removed in vacuo. The resultingresidue was suspended with water and extracted with EtOAc. The organicphase was washed with water, brine, dried (Na₂SO₄), filtered andconcentrated onto silica. Purification by flash chromatography (SiO₂;0-100% EtOAc in heptane) afforded 3.49 g (54%) of tert-butyl3-bromo-2,6-difluorophenylcarbamate: ¹H NMR (400 MHz, DMSO-d₆) δ1.34-1.54 (m, 9H) 7.17 (m, 1H) 7.63 (ddd, J=8.9, 7.9, 5.9 Hz, 1H).

Step 3. Preparation of 3-bromo-2,6-difluoroaniline

To a round bottom flask containing tert-butyl3-bromo-2,6-difluorophenylcarbamate (1 g, 3.3 mmol) was added DCM (3 mL)and TFA (3 mL). The reaction was stirred for 2 hours at roomtemperature. The volatiles were removed in vacuo, and the resultingresidue was neutralized with saturated aqueous NaHCO₃ solution to pH 8.The aqueous mixture was extracted with EtOAc. Organic phase was washedwith water, brine, dried (Na₂SO₄), filtered and concentrated ontosilica. Purification by flash chromatography (SiO₂; 0-50% EtOAc inheptane) afforded 425 mg (63%) of 3-bromo-2,6-difluoroaniline: LCMS(m/z) 208.0 (MH⁺); t_(R)=0.80 minute; ¹H NMR (400 MHz, DMSO-d₆) δ 5.54(s, 2H) 6.78 (ddd, J=9.0, 7.4, 5.5 Hz, 1H) 6.85-6.95 (m, 1H).

Step 4. Preparation of N-(3-bromo-2,6-difluorophenyl)propane-1-sulfonamide

To a solution of 3-bromo-2,6-difluoroaniline (425 mg, 2.04 mmol) in drypyridine (2.0 mL) was added 1-propanesulfonyl chloride (275 μL, 2.45mmol) and the resulting reaction was maintained overnight at roomtemperature. The reaction was partitioned between EtOAc and water, andthe layers separated. The aqueous portion was extracted with EtOAc andthe combined organic portions were washed with 10% aqueous citric acidsolution, water, brine, dried (Na₂SO₄), and concentrated to yield abrown viscous oil as a 2:1 mixture of 3-bromo-2,6-difluoroaniline andN-(3-bromo-2,6-difluorophenyl) propane-1-sulfonamide which was carriedforward without further purification: N-(3-bromo-2,6-difluorophenyl)propane-1-sulfonamide LCMS (m/z) not ionized (MH⁺); t_(R)=1.06 minutes.

Step 5. Preparation ofN-(2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(SM-14)

The mixture of 3-bromo-2,6-difluoroaniline andN-(3-bromo-2,6-difluorophenyl) propane-1-sulfonamide (560 mg, 2.69 mmol)was combined with bis(pinacolato)diboron (820 mg, 3.23 mmol),tricyclohexylphosphine (52.8 mg, 0.188 mmol), potassium acetate (396 mg,4.04 mmol), and Pd₂ dba₃ (74.0 mg, 0.081 mmol) in 1,4-dioxane (10 mL) togive a yellow suspension. The reaction mixture was heated in a oil bathto 120° C. for 2 hours whereupon LCMS indicated complete conversion. Thereaction was allowed to cool to room temperature and partitioned betweenEtOAc and water. The layers were separated and the aqueous portion wasextracted with EtOAc. The combine organic portions were washed withwater (2×), brine, dried (Na₂SO₄), and concentrated to give a dark brownoil as a mixture of boronate esters which was used without furtherpurification:N-(2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamideLCMS (m/z) 174.0 (MH⁺, boronic acid); t_(R)=0.33 minute.

Preparation of3-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-15)

Step 1. Preparation of 5-bromo-3-methoxy-2-methylaniline

This material was prepared from5-bromo-1-methoxy-2-methyl-3-nitrobenzene following the procedure usedfor SM-9, step 2: LCMS (m/z): 216.0 (MH⁺); t_(R)=0.65 minute.

Step 2. Preparation of3-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-15)

This material was prepared following the procedure used for SM-9, step3: LCMS (m/z): 264.3 (MH⁺); t_(R)=0.67 minute.

Preparation of5-chloro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-16)

Step 1. Preparation of 3-bromo-5-chloro-2-methylaniline

This material was prepared from 1-bromo-5-chloro-2-methyl-3-nitrobenzenefollowing the procedure used for SM-9, step 3 (96%): LCMS (m/z): 219.9(MH⁺); t_(R)=0.99 minute.

Step 2. Preparation of5-chloro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-16)

This material was prepared following the procedure used for SM-9, step3: LCMS (m/z) 268.1 (MH⁺); t_(R)=1.14 minutes.

Preparation of starting material3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (SM-17)

This material was prepared from 3-bromo-5-chloroaniline following asimilar procedure used for SM-9, step 3. The crude product was purifiedby flash chromatography (RediSep Cyano®, Teledyne ISCO, 0-50% EtOAc inhexanes) to afford3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (48%) asa pale orange solid: LCMS (m/z) 172.1 (MH⁺), t_(R)=0.33 minute.

Preparation of3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-18)

Step 1. Preparation of 1-bromo-3-(difluoromethoxy)-5-nitrobenzene

To a solution of 3-bromo-5-nitrophenol (3.1 g, 14.4 mmol) and powderedsodium hydroxide (0.63 g, 15.8 mmol) in DMF (14 mL), sodiumchlorodifluoroacetate (4.4 g, 28.7 mmol) was added in five portionsevery 0.5 hour to the warmed reaction mixture at to 55° C. The reactionwas maintained at to 55° C. for 1 day and then allowed to cool to roomtemperature. The reaction mixture was partitioned between EtOAc andwater, the layers separated, and the aqueous portion was extracted (2×25mL) EtOAc and the combined organic layers were washed with aqueous 1.0 MNaOH solution (3×25 mL), water (3×25 mL) and brine (50 mL). The organiclayer was dried (MgSO₄), and concentrated. The resulting residue waspurified by flash chromatography (SiO₂, 0-50% EtOAc in hexanes) toafford 1-bromo-3-(difluoromethoxy)-5-nitrobenzene (160 mg, 0.6 mmol). ¹HNMR (400 MHz, CDCl₃) δ 6.61 (t, J=71.6 Hz, 1H) 7.65 (s, 1H) 7.96 (s, 1H)8.21-8.31 (m, 1H).

Step 2. Synthesis of 3-bromo-5-(difluoromethoxy)aniline

This material was prepared following the procedure used for SM-9, step3. The crude product was purified by flash chromatography (SiO2, 0-30%EtOAc in hexanes) to furnish 3-bromo-5-(difluoromethoxy)aniline as alight brown oil (41% yield):

LCMS (m/z) 237.9 (MH⁺), t_(R)=0.81 minute; ¹H NMR (300 MHz, CDCl₃) δ3.83 (br s, 2H) 6.45 (t, 1H) 6.58-6.79 (m, 1H).

Step 3. Synthesis of3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-18)

This material was prepared following the procedure used for SM-9, step3: LCMS (m/z) 204.1 (MH⁺, boronic acid), t_(R)=0.33 minute.

Preparation of starting materialN-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-2-sulfonamide(SM-19)

Step 1. Preparation of N-(3-bromo-5-methylphenyl)propane-2-sulfonamide

To a solution of 3-bromo-5-methylaniline (500 mg, 2.2 mmol) in DCM (5mL), isopropylsulfonylchloride (0.3 mL, 2.7 mmol) was added, followed bythe addition of pyridine (0.45 mL, 5.6 mmol). The reaction was stirredat room temperature for 25 hours at which time it was quenched withwater and extracted with EtOAc. The organic layer was washed with brine,dried (MgSO₄), and absorbed onto silica. Purification by flashchromatography (SiO₂, 0-30% EtOAc in hexanes) affordedN-(3-bromo-5-methylphenyl)propane-2-sulfonamide (558 mg, 1.9 mmol, 85%)as a peach colored solid: ¹H NMR (400 MHz, CDCl₃) δ 1.41 (d, J=6.7 Hz,6H) 2.31 (s, 3H) 3.33 (m, 1H) 6.84 (br s, 1H) 6.97 (s, 1H) 7.10 (s, 1H)7.21 (s, 1H).

Step 2. Preparation ofN-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-2-sulfonamide

This material was prepared following the procedure used for SM-9, step 3and was used as is in the next step.

Preparation of2,5-dichloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-20)

Step 1. Preparation of 2,5-dichloro-3-nitrobenzoic acid

To a solution of 2,5-dichlorobenzoic acid (3 g, 15.7 mmol) in H₂SO₄ (16mL) at 0° C. was added dropwise fuming nitric acid (1.4 mL, 31.4 mmol)and the reaction mixture was stirred for 5 minutes at 0° C., and wasthen gradually allowed to warm to over 20 minutes. The reaction wastreated with ice water and extracted with EtOAc. The organic layer waswashed with water and brine then dried (Na₂SO₄), filtered andconcentrated to afford 3.54 g (48%) of 2,5-dichloro-3-nitrobenzoic acidwhich is contaminated with 3,6-dichloro-2-nitrobenzoic acid (40%): ¹HNMR (300 MHz, CD₃OD) δ 7.73 (s, 1H) 8.06 (d, J=2.6 Hz, 1H) 8.11 (d,J=2.6 Hz, 1H).

Step 2. Preparation of 1-bromo-2,5-dichloro-3-nitrobenzene

To an oven dried round bottom flask equipped with stir bar andcondenser, under nitrogen at room temperature was added2,5-dichloro-3-nitrobenzoic acid (3.54 g, 15.00 mmol as a mixture with3,6-dichloro-2-nitrobenzoic acid), mercuric oxide, red (4.87 g, 22.50mmol) and carbon tetrachloride (100 mL). The reaction mixture was heatedto 90° C. for 30 minutes with irradiation from a 150 W TYPE A utilitylight bulb. The reaction mixture was then cooled to approximately 60° C.and bromine (1.2 mL, 22.5 mmol) was added dropwise via a syringe. Thenitrogen atmosphere was replaced with an argon balloon and the reactionmixture was heated again to 90° C. for 4 hours with constant lightirradiation. The reaction mixture was then cooled to room temperature,quenched with saturated aqueous NaHCO₃ solution, stirred for 2 hours,filtered through Celite, and diluted with DCM. The two phases wereseparated and the aqueous mixture was extracted with DCM. The organicswere combined, washed with water, brine, dried (Na₂SO₄), andconcentrated to a pale yellow crystalline solid which was purified byflash chromatography (SiO₂, 0-15% EtOAc in heptane) to afford 1.83 g(29%) of 1-bromo-2,5-dichloro-3-nitrobenzene: ¹H NMR (300 MHz, CDCl₃) δ7.75 (d, J=2.3 Hz, 1H) 7.87 (d, J=2.3 Hz, 1H).

Step 3. Preparation of 3-bromo-2,5-dichloroaniline

This material was prepared according to the procedure used for SM-9,step 2 using 1-bromo-2,5-dichloro-3-nitrobenzene. Purification by flashchromatography (SiO₂, 0-30% EtOAc in heptane) provided3-bromo-2,5-dichloroaniline (24%): LCMS (m/z) 239.9 (MH⁺), t_(R)=1.03minutes; ¹H NMR (400 MHz, CDCl₃) δ 4.28 (br s, 2H) 6.71 (d, J=2.4 Hz,1H) 7.02 (d, J=2.4 Hz, 1H).

Step 4. Preparation of2,5-dichloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-20)

This material was prepared according to the procedure used for SM-9,step 3. LCMS (m/z): 287.9 (MH⁺); t_(R)=1.10 minutes.

Preparation of2-chloro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-21)

Step 1. Preparation of 3-bromo-2-chloro-5-methylaniline

To an Argon sparged solution of 1,3-dibromo-2-chloro-5-methylbenzene (5g, 17.6 mmol), benzophenone imine (3.1 mL, 18.5 mmol), sodiumtert-butoxide (2.53 g, 26.4 mmol) in toluene, (S)-BINAP (1.6 g, 2.6mmol) and Pd₂(dba)₃ (0.81 g, 0.88 mmol) were added and the reaction washeated in an oil bath. When the temperature reached 60° C. an exothermwas noted, with reflux of the solvent. Heating was maintained and thereaction was complete after 1.5 hours. The reaction mixture was cooled,diluted with Et₂O and stirred with Siliabond DMT (Pd scavenger), and wasthen filtered through Celite. The filtrate was washed with water, brine,dried (MgSO₄), and concentrated to afford a sticky brown residue. Theresidue was dissolved in THF (60 mL) and aqueous 6.0 M HCl solution wasadded. The reaction mixture was stirred for 30 minutes, partitioned withEt₂O and 1M NaOH was added until the aqueous layer was pH 9. The layerswere separated and the organic layer was washed with water, brine, dried(MgSO₄), and concentrated. Purification by flash chromatography (SiO₂,0-20% EtOAc in heptane) furnished 3-bromo-2-chloro-5-methylaniline (1.7g) with a small amount of benzophenone as a contaminant: ¹H NMR (300MHz, CDCl₃) δ 2.21 (s, 3H) 4.11 (br s, 2H) 6.52 (s, 1H) 6.85 (s, 1H).

Step 2. Preparation of2-chloro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

This material was prepared following the procedure used for SM-9, step3. ¹H NMR (300 MHz, CDCl₃) δ 1.26 (s, 8H) 1.36 (s, 10H) 2.22 (s, 3H)4.00 (br s, 2H) 6.65 (d, J=2.1 Hz, 1H) 6.89 (d, J=1.8 Hz, 1H).

Preparation of starting material2-fluoro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-22)

Step 1. Preparation of 3-bromo-2-fluoro-5-methylbenzoic acid

To a solution of diisopropylamine (1.8 mL, 12.7 mmol) in THF (20 mL) at−10° C., n-BuLi (0.68 g, 10.6 mmol) was added and the reaction wasstirred for 1 hour at −10° C. and was then cooled to −78° C. A solutionof 2-bromo-1-fluoro-4-methylbenzene (2.0 g, 10.6 mmol) in THF (10 mL)was added in dropwise and the reaction was stirred for 1 hour afterwhich excess solid carbon dioxide (4.76 g, 106 mmol) was added. After 30minutes the reaction mixture was allowed to warm to room temperature,allowing for pressure release, and was quenched with water. Theresulting layers were separated and the aqueous portion was extractedwith Et₂O. The aqueous layer was then acidified with aqueous 6.0 M HClsolution and the resulting white precipitate was extracted into Et₂O.The combined organic portions were dried (MgSO₄), and concentrated invacuo to afford 3-bromo-2-fluoro-5-methylbenzoic acid (2.1 g, 9.0 mmol,85%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 2.37 (s, 3H) 7.60 (dd,J=5.9, 1.8 Hz, 1H) 7.75 (dd, J=6.2, 1.8 Hz, 1H).

Step 2. Preparation of tert-butyl3-bromo-2-fluoro-5-methylphenylcarbamate

To a solution of 3-bromo-2-fluoro-5-methylbenzoic acid (2.1 g, 9.01mmol) in toluene (30 mL) and t-BuOH (15 mL), DIEA (1.9 mL, 10.8 mmol)and DPPA (2.4 mL, 11.3 mmol) were added and the reaction mixture washeated to and maintained at 120° C. for 24 hours. The reaction wasallowed to cool to room temperature and concentrated to afford a brownoil. The oil was partitioned between diethyl ether and water and theresulting layers separated. The diethyl ether layer was washed withwater, brine, dried (MgSO₄) and concentrated. Purification by flashchromatography (SiO₂, 0-5% EtOAc in heptane) provided tert-butyl3-bromo-2-fluoro-5-methylphenylcarbamate (985 mg, 3.2 mmol, 36%) as aclear pale yellow oil: LCMS (m/z) 247.9 (MH⁺-t-butyl); t_(R)=1.14minutes; ¹H NMR (300 MHz, CDCl₃) δ 1.53 (s, 9H) 2.29 (s, 3H) 6.67 (br s,1H) 6.98 (d, J=6.2 Hz, 1H) 7.88 (d, J=6.5 Hz, 1H).

Step 3. 3-Bromo-2-fluoro-5-methylaniline

To a solution of tert-butyl 3-bromo-2-fluoro-5-methylphenylcarbamate(985 mg, 3.24 mmol) in isopropyl alcohol (10 mL) was added concentratedaqueous HCl (˜12 M, 2.6 mL, 32.4 mmol) and the reaction mixture waswarmed to 60° C. for 2 hours, allowed to cool to room temperature, andthen concentrated in vacuo to afford a white solid. The solid wasdissolved in water and the resulting aqueous solution was neutralizedwith aqueous 1.0 M NaOH solution, and extracted with Et₂O. The organicphase was washed with brine, dried (MgSO₄) and concentrated to afford3-bromo-2-fluoro-5-methylaniline (594 mg, 2.91 mmol, 90%) which wascarried forward without further purification: ¹H NMR (300 MHz, CDCl₃) δ2.21 (s, 3H) 3.71 (br s, 2H) 6.51 (d, J=7.9 Hz, 1H) 6.70 (d, J=4.7 Hz,1H).

Step 4. Preparation of2-fluoro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-22)

This material was prepared following the procedure used for SM-9, step3: LCMS (m/z) 252.0 (MH⁺); t_(R)=0.83 minute.

Preparation of starting material2-chloro-4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-20)

Step 1. Preparation of 2-(2-bromo-3-chloro-1-fluoro-4-nitrobenzene)

2-Bromo-1-chloro-3-fluorobenzene (3.4 g, 16.2 mmol) was dispersed inconcentrated sulfuric acid (10 mL), NaNO₃ (1.52 g, 17.9 mmol) was thenadded into the mixture in portions with stirring at 0° C. The reactionmixture was then stirred at room temperature overnight. The reaction waspoured into ice water (60 mL) and allowed to stand overnight. Theresulting precipitated white solid was collected by filtration, washedwith water, and dissolved in EtOAc. The organic solution was washed withsaturated aqueous Na₂CO₃ solution, brine, dried (Na₂SO₄), andconcentrated to afford 3.8 g of a solid residue (1:7 mixture of tworegioisomers, the major being the desired one). The solid was dissolvedin HOAc (15 mL), cooled to 5° C., and iron powder (2.7 g, 48 mmol) wasadded in portions. After addition, the reaction mixture was stirred atroom temperature overnight, diluted in EtOAc and then filtered through apad of Celite. The filtrate was made alkaline (pH˜12) with aqueous 12 NNaOH solution and the resulting gelatinous mixture was filtered throughCelite. The filtrate partitioned upon standing and the layers separated.The aqueous portion was extracted with EtOAc (2×) and the combinedorganic portions were washed with brine, dried (Na₂SO₄) andconcentrated. Purification by flash chromatography (SiO₂, 0-70% EtOAc inheptane) gave the desired 3-bromo-2-chloro-4-fluoroaniline (2.2 g, 9.0mmol, 56%): LCMS (m/z) 223.8 (MH⁺); t_(R)=0.89 minute; ¹H NMR (400 MHz,CDCl₃) δ 6.92-6.88 (m, 1H), 6.71-6.66 (m, 1H), 4.05 (br s 2H).

Step 2. Preparation of 4(2-chloro-4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-23)

This compound was prepared using the same procedure as in startingmaterial SM-9, step 3: LCMS (m/z) 272.0 (MH⁺); t_(R)=0.95 minute.

Preparation of Intermediate (S)-tert-butyl1-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(I-1a)

Step 1. Preparation of 2-cyclopropyl-1H-imidazole

Glyoxal (40% in water) (86 mL, 749 mmol) in water (200 mL) was added toa cooled solution (5° C.) of cyclopropanecarbaldehyde (50.0 mL, 713mmol) in methanol (100 mL) to give a colorless solution. Ammoniumhydroxide (28% aq, 397 mL, 2900 mmol) was added dropwise over 1 hour at0-5° C. The reaction was stirred for 3 hours at 0° C. and then allowedto warm to room temperature overnight. Brine (200 mL) was added to thereaction and extracted with EtOAc (4×400 mL, 4×600 mL). The combinedorganic layers were dried (Na₂SO₄) and concentrated to afford2-cyclopropyl-1H-imidazole as a beige solid (70.1 g, 648 mmol, 91%).LCMS (m/z) 109.0 (MH⁺), t_(R)=0.22 minute; ¹H NMR (400 MHz, DMSO-d6) δ0.73-0.81 (m, 2H), 0.81-0.88 (m, 2H), 1.85-1.95 (m, 1H), 6.78 (br s,2H), 11.65 (br s, 1H).

Step 2. Preparation of 4,5-dibromo-2-cyclopropyl-1H-imidazole

Bromine (61 mL, 1190 mmol) was added dropwise over 2 hours to a cooledmixture of 2-cyclopropyl-1H-imidazole (70.5 g, 652 mmol) and KHCO₃ (118g, 1179 mmol) in DMF (360 mL) at 0° C. Additional KHCO₃ (20 g, 200 mmol)was added and the reaction was stirred for another 45 minutes at 0° C.Water (1.5 L) was added dropwise over 45 minutes and the resultingorange slurry was filtered cold. The solids were washed with water(4×150 mL) and dried in a vacuum oven at 50° C. for 24 hours to furnish4,5-dibromo-2-cyclopropyl-1H-imidazole as a tan solid (122 g, 459 mmol,70%). LCMS (m/z) 264.8 (MH⁺), t_(R)=0.51 minute; ¹H NMR (400 MHz,DMSO-d6) δ 0.77-0.81 (m, 2H), 0.86-0.91 (m, 2H), 1.83-1.92 (m, 1H),12.86 (br s, 1H).

Step 3. Preparation of4,5-dibromo-2-cyclopropyl-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazole

A solution of 4,5-dibromo-2-cyclopropyl-1H-imidazole (60 g, 226 mmol) inTHF (150 mL) was added dropwise over 50 minutes under nitrogen to astirring mixture of sodium hydride (95%, 6.3 g, 250 mmol) in dry THF(150 mL) at 0° C. The reaction mixture was stirred 30 minutes and2-(trimethylsilyl)ethoxymethylchloride (SEMCl, 40 mL, 38 g, 226 mmol)was added dropwise over 50 minutes at 0° C. After stirring for 1 hour,the reaction was slowly quenched with water (20 mL) and added EtOAc (500mL). The mixture was washed with water (2×750 mL) and the combinedaqueous portions were back extracted with EtOAc (200 mL). The combinedorganic portions were washed with brine (1 L), dried (Na₂SO₄), andconcentrated. The resulting residue was dissolved in heptane (200 mL)and the resulting solution was passed through a pad of silica gel,eluting with heptane (4×500 mL) and EtOAc-heptane (1:4, 2×250 mL) togive4,5-dibromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(79 g, 199 mmol, 88%) as a pale yellow solid after concentration: LCMS(m/z) 394.9 (MH⁺), t_(R)=1.20 minutes, ¹H NMR (400 MHz, CDCl₃) δ ppm−0.04-0.05 (m, 9H), 0.87-1.12 (m, 6H), 1.88-2.04 (m, 1H), 3.55-3.66 (m,2H), 5.37 (s, 2H).

Step 4. Preparation of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloro-4,5-dihydropyrimidine

Butyllithium (2.0 M in pentane, 31 mL, 62 mmol) was added dropwise over40 minutes to a solution of4,5-dibromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(23.4 g, 59.1 mmol) in THF (175 mL) at −78° C. Reaction was stirred at−78° C. for 10 minutes. After this time, an aliquot of the reaction wasquenched with water and complete lithiation was verified by LCMS. Asolution of 2-chloropyrimidine (8.12 g, 70.9 mmol) in THF (20 mL) wasadded dropwise and stirred for 30 minutes. LCMS analysis indicatedcomplete reaction. The reaction was quenched with saturated aqueousNH₄Cl solution (20 mL), allowed to warm to 0° C., and partitionedbetween water (500 mL) and EtOAc (500 mL). The layers were separated andthe organic portion was washed with water-brine (500 mL) and brine (500mL), then dried (Na₂SO₄) and concentrated to a yellow oil.

The crude residue was suspended in a mixture of EtOAc-hexanes (1:5, 50mL) and heptane (50 mL) and then sonicated for 2 minutes. The resultingsuspension was allowed to settle at 0° C. for 1 hour. The collectedsolids were washed with cold EtOAc-heptane (1:5, 50 mL) to furnish 19.6g of4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloro-4,5-dihydropyrimidineas a white solid. The combined filtrates were purified by flashchromatography (SiO₂, 20-70% EtOAc in heptane) to provide an additional2.05 g of product (21.65 g, 50.1 mmol, 85%): LCMS (m/z) 431.0 (MH⁺),t_(R)=0.78 minute; ¹H NMR (400 MHz, DMSO-d6) δ ppm −0.02 (s, 9H),0.74-0.99 (m, 6H), 1.99-2.16 (m, 1H), 3.52 (m, 2H), 4.48 (br s, 1H),5.45 (s, 2H), 5.55 (dd, J=2.7, 1.6 Hz, 1H), 6.14 (dd, J=7.4, 1.6 Hz,1H), 9.06-9.50 (br s, 1H).

Step 5. Preparation of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine

4-(4-Bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloro-4,5-dihydropyrimidine(21.65 g, 50.1 mmol) and manganese dioxide (43.6 g, 501 mmol) in EtOAc(240 mL) was heated at reflux for 2.5 hours. The reaction mixture wascooled to room temperature and filtered through Celite. The filtrateswere concentrated and the residue purified by flash columnchromatography (10-40% EtOAc in heptane) to afford4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidineas a yellow oil (17.8 g, 41.4 mmol, 83%). LCMS (m/z) 429.0 (MH⁺),t_(R)=1.24 minutes; ¹H NMR (400 MHz, CDCl₃) δ −0.06 (s, 9H), 0.82-0.90(m, 2H), 1.04-1.11 (m, 2H), 1.14-1.20 (m, 2H), 2.06 (m, 1H), 3.55-3.62(m, 2H), 5.92 (s, 2H), 7.92 (d, J=5.5 Hz, 1H), 8.62 (d, J=5.5 Hz, 1H).

Step 6. Preparation of(S)-tert-butyl-1-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(I-1a)

A mixture of4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine(5.50 g, 12.8 mmol), (S)-tert-butyl 1-aminopropan-2-ylcarbamate (SM-1,2.68 g, 15.4 mmol), diisopropylethylamine (2.68 mL, 15.4 mmol) andsodium carbonate (2.71 g, 25.6 mmol) in NMP (8 mL) was heated with 110°C. oil bath for 3.5 hours and LCMS analysis of an aliquot indicatedreaction completion with desired product. The reaction was allowed tocool to ambient temperature, then partitioned between EtOAc (20 mL) andwater (60 mL). The EtOAc layer was washed with water (60 mL), dried(Na₂SO₄), and concentrated to a light yellow foam (6.89 g, 12.1 mmol). Asmall portion of material was further purified by flash chromatography(SiO₂, EtOAc in heptane): LCMS (m/z) 567.3 (MH⁺), t_(R)=1.03 minutes; ¹HNMR (CDCl₃, 300 MHz) δ −0.09 (s, 9H), 0.80 (t, J=8.2 Hz, 2H), 0.98-1.07(m, 2H), 1.10-1.18 (m, 2H), 1.21 (t, J=6.5 Hz, 3H), 1.40 (s, 9H),1.91-2.08 (m, 1H), 3.41 (t, J=8.2 Hz, 2H), 3.44-3.59 (m, 2H), 3.82-4.01(m, 1H), 4.65-4.87 (m, 1H), 5.41-5.61 (m, 1H), 5.78-5.99 (m, 2H), 7.10(d, J=5.0 Hz, 1H), 8.33 (d, J=5.2 Hz, 1H).

Preparation of Intermediate (S)-methyl1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(I-1b)

Step 1. Preparation of(S)—N1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine,hydrogen chloride salt

A solution of (S)-tert-butyl1-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(15.5 g, 27.3 mmol) in MeOH (60 mL) was treated with aqueous conc. HCl(37%, 10 mL, 122 mmol) at 60° C. for 3.5 hours. LCMS of an aliquotindicated complete conversion. The reaction mixture was concentrated invacuo to obtain(S)—N1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamineas the HCl salt (13.3 g): LCMS (m/z) 337.1 (MH⁺), t_(R)=0.41 minute.

Step 2. Synthesis of (S)-methyl1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(I-1b)

A mixture of(S)—N1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine(13.3 g, 27.3 mmol, assumed theoretical yield) in 1:1 THF-water (200 mL)was cooled to 0° C. and solid NaHCO₃ (20.6 g, 245 mmol) was added inportions. Methyl chloroformate (3.74 mL, 27.3 mmol) was added dropwiseover 20 minutes and stirred for an additional 30 minutes. LCMS of analiquot indicated complete reaction. Water (300 mL) was added and theresulting mixture was extracted with EtOAc (3×500 mL). The EtOAc layerwas washed with brine (2×1 L), dried (Na₂SO₄) and concentrated. Theresulting solid was suspended in a mixture of EtOAc (7 mL) and ethylether (25 mL) and the resulting suspension was allowed to settle at 0°C. The solids were collected and washed with cold Et₂O (20 mL) to afford(S)-methyl1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(9.56 g, 24.1 mmol, 89%) as an off-white solid: LCMS (m/z) 395.1 (MH⁺),t_(R)=0.61 minute; ¹H NMR (400 MHz, CDCl₃) δ 0.91-1.03 (m, 2H),1.08-1.19 (m, 2H), 1.22 (d, J=6.6 Hz, 3H), 1.77 (br s, 1H), 2.13-2.26(m, 1H), 2.70-2.90 (m, 1H), 3.70 (s, 3H), 3.90-4.03 (m, 1H), 4.18-4.32(m, 1H), 4.46-4.86 (m, 1H), 5.48-5.60 (m, 1H), 7.46 (d, J=5.5 Hz, 1H),8.24 (d, J=5.4 Hz, 1H).

Preparation of Intermediate3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile(I-1c)

A mixture of4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine(I-1a, step 5, 3.50 g, 8.14 mmol), 3-aminopropionitrile (1.79 mL, 24.4mmol), diisopropylethylamine (2.84 ml, 16.3 mmol) and Na₂CO₃ (1.73 g,16.3 mmol) in dry NMP (4 mL) was heated at 90° C. for 8 hours. Thereaction was cooled to room temperature, and then partitioned betweenEtOAc (100 mL) and water (100 mL), and the layers separated. The organicportion was washed with water (100 mL), saturated aqueous NaHCO₃solution (100 ml), brine (100 mL), dried (Na₂SO₄) and concentrated. Thecrude residue was purified by flash chromatography (SiO₂, 0-50% EtOAc inheptane) to furnish3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)propanenitrileas a pale yellow foam (2.91 g, 6.28 mmol). LCMS (m/z) 463.1 (MH⁺),t_(R)=0.98 minute, ¹H NMR (CDCl₃) δ ppm −0.09 (s, 9H) 0.73-0.85 (m, 2H)0.99-1.11 (m, 2H) 1.12-1.21 (m, 2H) 1.90-2.05 (m, 1H) 2.75 (t, J=6.7 Hz,2H) 3.36-3.48 (m, 2H) 3.76 (q, J=6.5 Hz, 3H) 5.50 (br s, 1H) 5.85 (s,2H) 7.20 (d, J=5.1 Hz, 1H) 8.37 (d, J=5.1 Hz, 1H).

Preparation of Intermediate3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)-2-methylpropanenitrile(I-1d)

A solution of4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine(2.5 g, 5.8 mmol), DIEA (2.0 mL, 11.6 mmol), and3-amino-2-methylpropanenitrile (1.49 g, 17.7 mmol) in NMP (10 mL) wastreated with Na₂CO₃ (1.23 g, 11.6 mmol) and the resulting reactionmixture heated at 90° C. overnight. The reaction was allowed to cool toroom temperature and was partitioned between EtOAc (75 mL) and water(100 mL). The layers were separated and the organic portion was washedwith saturated aqueous NaHCO₃ solution (100 mL), brine (150 mL), dried(Na₂SO₄) and concentrated to a brown residue. Purification by flashchromatography (0-50% EtOAc-heptane) afforded3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)-2-methylpropanenitrile(2.79 g, 5.8 mmol) as a white solid: LCMS (m/z) 477.1 (MH⁺), t_(R)=0.98minute.

Preparation of Intermediate1-((4-(4-Bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)methyl)cyclopropanecarbonitrile(I-1e)

A mixture of 1-(aminomethyl)cyclopropanecarbonitrile (0.67 g, 7.0 mmol),4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine(2.01 g, 4.7 mmol), DIEA (1.64 ml, 9.35 mmol), Na₂CO₃ (0.99 g, 9.4 mmol)and NMP (2 mL) was heated at 110° C. for 25 hours. The reaction mixturewas allowed to cool to room temperature and partitioned between EtOAc(10 mL) and water (20 mL). The layers were separated and the organicportion was sequentially washed with water (20 mL), brine (10 mL), andconcentrated. The resulting residue was purified by flash chromatographyon silica gel eluting with an EtOAc-heptane (0-50%) gradient to provide1-((4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)methyl)cyclopropanecarbonitrile(1.50 g, 3.06 mmol, 66%) as a white foam. LCMS (m/z) 491.1 (MH⁺),t_(R)=0.99 minute.

Preparation of Intermediate4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-amine(I-1g)

4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine(1 g, 2.4 mmol) was combined with aqueous 28% NH₄OH solution (8 mL) in1,4-dioxane (8 mL) and the resulting mixture was split evenly betweentwo reaction vials. Each was irradiated in a microwave reactor for 40minutes at 130° C. TLC analysis indicated complete reaction. Thecombined reactions were then diluted with water (100 mL) followed byextraction with EtOAc (100 mL). The EtOAc layer was washed with brinethen dried (Na₂SO₄), and concentrated. Purification of the resultingresidue by flash chromatography on silica gel using an EtOAc-hexanesgradient (0 to 60%) provided 0.87 g of (2.1 mmol, 91%) of4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-amineas a white solid: LCMS (m/z): 410.0 (MH⁺), t_(R)=0.81 minute.

Preparation of intermediate4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidine(I-1h)

Step 1. Preparation of4-(2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrimidine

A solution of4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidineand ammonium formate (12.12 g, 192 mmol) in MeOH (20 mL) was spargedwith Argon for 5 minutes. Pd/C (200 mg, 4.80 mmol) was added into themixture and it was the reaction was stirred at room temperature for 5hours. LCMS analysis of an aliquot indicated complete conversion. Thereaction mixture was filtered through a pad of Celite and the filtercake was washed thoroughly with EtOAc. The combined filtrates wereconcentrated and the resulting residue was purified by flashchromatography using an EtOAc-hexanes gradient (0-100%) to furnish4-(2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrimidine(1.36 g, 4.30 mmol, 89% yield) as a light yellow sticky oil: LCMS (m/z)317.3 (MH⁺), t_(R)=0.71 minute.

Step 2. Preparation of4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilylethoxy)methyl)-1H-imidazol-5-yl)pyrimidine(I-1h)

Bromine was added to a cooled solution of4-(2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrimidine(1.36 g, 4.30 mmol) in DCM at 0° C. followed by saturated aqueous Na₂CO₃solution (16 mL, 4.30 mmol). The reaction mixture was stirred for 3hours at room temperature. After the reaction was judged complete byLCMS analysis, the reaction mixture was allowed to stand and partition.The resulting layers were separated and the aqueous layer was extractedwith EtOAc (2×). The combine organic layers were washed with brine,dried (Na₂SO₄), and concentrated. The resulting residue was by flashchromatography using an EtOAc-hexanes gradient (20-80%) to give4-(5-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrimidine(1.07 g, 2.71 mmol, 63%) as a yellow oil: LCMS (m/z): 395.0 (MH⁺),t_(R)=1.09 minutes; ¹H NMR (400 MHz, CDCl₃) δ 0.00 (s, 9H) 0.80-1.50 (m,4H) 2.06-2.25 (m, 1H) 3.49-3.65 (m, 2H) 6.05 (s, 2H) 7.95-8.07 (m, 1H)8.82-8.94 (m, 1H) 9.27-9.34 (m, 1H).

Preparation of intermediate3-(5-(2-chloropyrimidin-4-yl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-imidazol-4-yl)-2-fluoroaniline (I-1i)

To a microwave vial with stir bar was added4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (I-1a, step 5, 0.55 g, 1.3mmol), 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(0.61 g, 2.6 mmol), 2.0 M aqueous sodium carbonate solution (3.2 mL, 6.4mmol) and DME (6.4 mL). The resulting mixture was sparged with nitrogenfollowed by the addition of PdCl₂(dppf).DCM adduct (0.052 g, 0.06 mmol).The reaction was sealed and irradiated in microwave reactor for 20minutes at 120° C. The reaction mixture was diluted with a saturatedaqueous NH₄Cl solution and extracted with EtOAc. The organic phase waswashed with water, brine, dried (Na₂SO₄), filtered, concentrated, andadsorbed onto silica gel. Purification by flash chromatography (SiO₂,0-100% EtOAc in heptane) yielded3-(5-(2-chloropyrimidin-4-yl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroaniline (223 mg, 0.48 mmol, 38%) as aviscous yellow oil: LCMS (m/z) 460.1 (MH⁺), t_(R)=0.95 minute.

Preparation of intermediate (S)-methyl1-(4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(I-2a)

Step 1. Preparation of 2-tert-butylimidazole

A solution of glyoxal (40% in water, 16.4 g, 113.4 mmol) in water (180mL) was added to trimethylacetaldehyde (12.4 ml, 112.6 mmol) and theresulting solution was cooled to 10° C. in an ice/water bath. To thissolution was added ammonium hydroxide solution (28% in water, 56 mL)with stirring. The reaction mixture was stirred overnight and theresulting precipitate was filtered and dried to afford 12.1 g of thetitle compound as a white crystalline solid. LCMS (m/z): 125.10 (MH⁺),t_(R)=0.26 minute; ¹H NMR (300 MHz, CD₃OD) δ 6.86 (2H, s), 1.32 (9H, s).

Step 2. Preparation of 4,5-dibromo-2-tert-butyl-1H-imidazole

Bromine (8.4 g, 52.42 mmol) was added dropwise to a mixture of2-t-butylimidazole (2.6 grams, 20.97 mmol) and potassium bicarbonate(5.4 g, 52.42 mmol) in dry DMF (25 mL). The reaction mixture was thenstirred at 70° C. for 4 hours. The reaction was allowed to cool to roomtemperature and was then filtered through a sintered funnel. Thecollected filtrate was cooled in an ice bath and diluted with cold water(100 mL) with stirring. The resultant precipitate was collected byfiltration, washed with cold water (3×) and dried under vacuum tofurnish 2.79 g of 4,5-dibromo-2-tert-butyl-1H-imidazole as a lightyellow solid: LCMS (m/z): 281.0 (MH⁺), t_(R)=0.63 minute; ¹H NMR (300MHz, DMSO-d₆) δ 1.23 (9H, s).

Step 3. Preparation of4,5-Dibromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

To a cooled solution of 2-t-butyl-4,5-dibromoimidazole (1.4 grams, 5.0mmol; Example 5, Step 2) in dry THF (10 mL) at 0° C. was added sodiumhydride (95%, 0.15 grams, 6.0 mmol) portion wise. The reaction mixturewas stirred for 10 minutes at 0° C., at room temperature for 40 minutes.The reaction was re-cooled to 0° C. and SEM-chloride (0.97 ml, 5.5 mmol)was added in dropwise. The reaction mixture was stirred overnightallowing the ice bath to expire and poured into a mixture of water (30mL) and EtOAc (50 mL). The resulting layers were partitioned andseparated. The organic portion was washed with brine, then water, dried(Na₂SO₄), and concentrated. The remaining residue was purified by flashchromatography (SiO₂, 0-10% EtOAc in hexanes) to provide 2.1 g of4,5-dibromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole:LCMS (m/z): 412.9 (MH⁺), t_(R)=1.320 minutes; ¹H NMR (400 MHz, CDCl₃) δ8.75 (dd, 1H,), 7.92 (dd, 1H,), 5.90 (s, 2H), 3.51 (m, 2H), 1.55 (s,9H), 0.82 (m, 2H), 0.08 (s, 9H).

Step 4. Preparation of4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine

n-BuLi (1.5 M in hexane, 40 mL, 60 mmol) was added dropwise to a cooledsolution of4,5-dibromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(23.6 g, 57.2 mmol) in anhydrous THF (250 mL) at −78° C. After 30minutes at −78° C., a solution of 2-chloropyrimidine (7.21 g, 63.0 mmol)in anhydrous THF (2 mL) was added dropwise and the reaction was stirredat −78° C. for 1 hour. The reaction was quenched by the addition ofsaturated aqueous NH₄Cl solution and allowed to warm to roomtemperature. The mixture was partitioned with EtOAc and the layersseparated. The aqueous portion was extracted with EtOAc (3×) and thecombine organic layers were washed with water, brine, dried (MgSO₄), andconcentrated. The resulting residue was dissolved in EtOAc, treated withMnO₂ (5.2 g, 60 mmol), and heated to reflux for 3 hours. The reactionwas allowed to cool to room temperature and filtered through Celite. Thefilter cake was washed thoroughly with EtOAc and the combine filtrateswere concentrated. The remaining residue was purified by flashchromatography (SiO₂, 0-10% EtOAc in hexanes) to give 10 g (37%) of4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine:LCMS (m/z): 445.0 (MH⁺), t_(R)=1.35 minutes. ¹H NMR (400 MHz, CDCl₃) δ8.64 (d, J=5.3 Hz, 1H), 7.83 (d, J=5.3 Hz, 1H), 5.85 (s, 2H), 3.45 (m,2H), 1.49 (s, 9H), 0.76 (m, 2H), −0.08 (s, 9H).

Step 5. Preparation of (S)-tert-butyl1-(4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(I-2a)

A mixture of4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine(2.0 g, 4.5 mmol;), (S)-tert-butyl-1-aminopropan-2-ylcarbamate (SM-1,1.0 g, 5.8 mmol), and diisopropylethyl amine (2.4 mL, 13.5 mmol) in dryacetonitrile was heated at 85° C. for 16 hours. An additional charge of(S)-tert-butyl-1-aminopropan-2-ylcarbamate (145 mg, 0.8 mmol, SM-1) wasadded and the reaction was maintained at 85° C. for 5 hours. Afterallowing to cool to room temperature, the reaction was diluted withEtOAc (40 mL), washed with water (2×15 mL), dried (Na₂SO₄), andconcentrated to provide 2.6 g of (S)-tert-butyl (5)-tert-butyl1-(4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamatewhich was carried forward without further purification: LCMS (m/z):583.0 (MH⁺), t_(R)=1.18 minutes.

Preparation of intermediate (S)-methyl1-(4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(I-2b)

To a solution of (S)-tert-butyl1-(4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (2.66g, 3.94 mmol, Example 7, Step 1) in MeOH (17 mL) was added aqueousconcentrated HCl (1.97 mL, 23.65 mmol) and the resulting reaction wasstirred at 60° C. for 1 hour. The reaction was allowed to cool to roomtemperature and concentrated in vacuo to give 2.28 g of crude residue.This material was then suspended in 1:1 THF-water (100 mL) followed bythe addition of NaHCO₃ (1.66 g, 19.70 mmol). The mixture was cooled to5° C. and methyl chloroformate (1.0 M in THF, 4.33 mL, 4.33 mmol) wasadded dropwise. After 50 minutes, an additional charge of methylchloroformate (1.0 M in THF, 4.33 mL, 4.33 mmol) was added and thereaction maintained for 45 minutes at 0° C. The reaction was quenchedwith water (300 mL) and the resulting layers were separated. The aqueousphase was extracted with EtOAc (2×200 mL) and the combined organicportions were washed with brine (2×400 mL), dried (Na₂SO₄), andconcentrated. The resulting residue was triturated with 1:4EtOAc-hexanes (10 mL) and washed with ether to provide 958 mg of(5)-methyl1-(4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate:LCMS (m/z) 411.0 (MH⁺), t_(R)=0.65 minute.

Preparation of intermediate (S)-methyl1-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(I-3a)

Step 1. Preparation of 2-(1-methylcyclopropyl)-1H-imidazole

Pyridinium chlorochromate (PCC, 28.95 g, 134.0 mmol) was added to(1-methylcyclopropyl)methanol (9.62 g, 112.0 mmol) in THF (90 mL). Thethick, black reaction mixture was stirred at room temperature for 2hours. The reaction was filtered through Celite, and the filter pad waswashed with THF (15 mL). Methanol, glyoxal and ammonium hydroxide addedsequentially to the filtrate, and the reaction was stirred at roomtemperature overnight. The reaction mixture was concentrated until whatremained was the water layer which contained solids. The solids werefiltered and washed with water (10 mL). The tan solids were air driedand then dried under high vacuum to give the product as a light brownsolid (3.74 g). The aqueous filtrate was extracted with EtOAc (3×500mL). The organic layers were combined, dried (Na₂SO₄) and concentratedto give additional product as a brown solid (2.92 g) which was usedwithout further purification: LCMS (m/z) 123.0 (MH⁺), t_(R)=0.26 minute.

Step 2. Preparation of 4,5-dibromo-2-(1-methylcyclopropyl)-1H-imidazole

To a mixture of 2-(1-methylcyclopropyl)-1H-imidazole (6.66 g, 54.5 mmol)and potassium carbonate (18.83 g, 136.0 mmol) in THF (100 mL) at roomtemperature was added NBS (19.40 g, 109 mmol) portionwise. The reactionmixture became warm so a dry ice-acetone bath was used to cool thereaction during the addition. The resultant mixture was allowed to warmto room temperature and stirred for 3.5 hours. The reaction mixture wasthen diluted with EtOAc, washed sequentially with aqueous 50% Na₂S₂O₃solution (2 X), water, brine, dried (Na₂SO₄) and concentrated to a lighttan solid. The crude material was purified by dissolving in EtOAc andfiltering through a pad of silica gel. The ethyl acetate fraction wasconcentrated and further purified by trituration with Et₂O to give4,5-dibromo-2-(1-methylcyclopropyl)-1H-imidazole as a white solid (10.44g): LCMS (m/z) 279.0 (MH⁺), t_(R)=0.56 minute.

Step 3. Preparation of4,5-dibromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

A 250 mL round-bottom flask was purged with N₂ and charged with NaH(95%, 0.33 g, 13.1 mmol). THF (15 mL) added, and the mixture cooled to0° C. After 5 minutes, a solution of4,5-dibromo-2-(1-methylcyclopropyl)-1H-imidazole (3.0 g, 10.7 mmol) inTHF (20 mL) was added dropwise from an addition funnel over 5 minutes.The light tan solution was stirred at 0° C. for 25 minutes and SEMCl(2.1 mL, 11.8 mmol) was then added dropwise over 2 minutes. After 5minutes, ice bath was removed, and the reaction stirred at roomtemperature. After stirring 2 hours, LCMS indicated 90% conversion.Another 0.3 mL of SEMCl (0.3 mL, 1.7 mmol) was added. LCMS indicatesthat the reaction has not proceeded; additional NaH (95%, 51 mg, 2.0mmol) was added with concomitant gas evolution. After 15 minutes, LCMSindicated complete reaction. The reaction was quenched with water (1mL). Heptane (250 mL) was added and organic layer was washed with water(200 mL). The aqueous layer was extracted with heptane (100 mL), and thecombined organic layers were washed with water and brine, dried(Na₂SO₄), and concentrated to give 4.46 g of crude material. The crudematerial was purified by flash chromatography (SiO₂; 0-25% EtOAc inheptane) to give the product (3.45 g) as a light yellow oil: LCMS (m/z)409.0 (MH⁺), t_(R)=1.27 minutes.

Step 4. Preparation of4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine

To a solution of4,5-dibromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(3.45 g, 6.7 mmol) in THF (50 mL) at −78° C. under nitrogen was addedn-BuLi (2.0 M in pentane, 4.5 mL, 9.0 mmol), dropwise over 5 minutes.After 10 minutes, LCMS indicated complete lithiation. A solution of2-chloropyrimidine (1.07 g, 9.3 mmol) in THF (20 mL) was added quicklyfrom an addition funnel over one minute. The reaction was stirred at−78° C. for 1 hour and LCMS indicated complete reaction. The reactionwas slowly quenched with 1:1 water-THF solution (50 mL) from an additionfunnel, keeping the temperature between −40° C. and −35° C. After 15minutes of stirring, a solution of DDQ (2.31 g, 10.2 mmol) in THF (100mL) was added slowly, and the mixture was stirred for 15 minutes underice water cooling. Aqueous 2.0 N NaOH solution (50 mL) was then addedfollowed by 1:1 water-THF solution (50 mL). The resulting mixture waspartitioned with EtOAc and the layers separated. The organic layer waswashed with water (2×), brine (2×), dried (Na₂SO₄), and concentrated togive a brown oil (5.2 g). The crude material was purified by flashchromatography (SiO₂, 0-100% of EtOAc in heptane) to furnish4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine(2.55 g, ˜80% purity by LCMS): LCMS (m/z) 443.0 (MH⁺), t_(R)=1.18minutes.

Step 5. Preparation of (S)-tert-butyl1-(4-(4-bromo-2-(1-methylcyclopropyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate

A mixture of4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine(2.55 g, 5.75 mmol), (S)-tert-butyl 1-aminopropan-2-ylcarbamate (1.95 g,11.2 mmol) and diisopropyl ethylamine (3.3 mL, 18.6 mmol) in dry ACN (10mL) was stirred at 80° C. for 18 hours, and then at room temperatureover 2 days. The reaction mixture was diluted with EtOAc, washed withwater (2×), brine, dried (Na₂SO₄), and concentrated to give a yellow oil(4.68 g). The crude material was purified by flash chromatography (SiO₂,0-60% EtOAc in heptane) to provide (S)-tert-butyl1-(4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(2.46 g, 5.5 mmol) as a white foam: LCMS (m/z) 581.1 (MH⁺), t_(R)=1.00minute.

Step 6. Preparation of(S)—N1-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine

A mixture of (S)-tert-butyl1-(4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(2.46 g, 4.23 mmol) in concentrated HCl (1.3 mL) and MeOH (20 mL) wasstirred at room temperature overnight. LCMS indicated only 30%conversion; the reaction was then heated at 60° C. for 4 hours andstirred overnight at room temperature. LCMS indicated completeconversion and the reaction mixture was concentrated to a yellow solidto afford the crude(S)—N1-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine(2.02 g) as the HCl salt which is used in next step withoutpurification: LCMS (m/z) 351.1 (MH⁺), t_(R)=0.45 minute.

Step 7. Preparation of (S)-methyl1-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-pyrimidin-2-ylamino)propan-2-ylcarbamate(I-3a)

A solution of(S)—N1-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine(2.02 g, 5.8 mmol) in THF-water (1:1, 60 mL) was cooled to 0° C. andthen solid NaHCO₃ (2.5 g, 30 mmol) was added with concomitant frothing.After 5 minutes a THF solution of methyl chloroformate (0.35 mL, 0.44 g,4.60 mmol, freshly prepared 1.0 M solution) was added dropwise to themixture. After 20 minutes, LCMS indicated only ˜70% conversion.Additional methylchloroformate solution (0.3 M in THF, 5 mL, 1.5 mmol)was added over 5 minutes. The reaction was maintained overnight,allowing the cooling bath to expire. LCMS indicated ˜90% conversion andadditional methylchloroformate solution (0.3 M in THF, 5 mL, 1.5 mmol)at 0° C. over 5 minutes. After stirring at room temperature for 1 hour,LCMS indicated complete reaction. The reaction mixture was extractedwith EtOAc. The organic phase was washed with brine and dried (Na₂SO₄),and concentrated to give (S)-methyl1-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamateas a yellow solid (1.65 g): LCMS (m/z) 409.1 (MH⁺), t_(R)=0.62 minute.

Preparation of intermediate3-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile(I-3b)

Step 1. Preparation of3-(4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile

Solid Na₂CO₃ (1.11 g, 10.5 mmol) was added to a solution of4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine(I-3a, step 4, 2.33 g, 5.2 mmol), DIEA (1.8 mL, 10.5 mmol), and3-aminopropionitrile (1.2 mL, 15.7 mmol) in NMP (3 mL) and the resultingreaction mixture was heated to 90° C. After 5 hours, LCMS indicatedcomplete reaction and the reaction was allowed to cool to roomtemperature. EtOAc (75 mL) was added the organic phase was washed withwater (100 mL), dilute aqueous NaHCO₃ solution (100 mL), brine (150 mL),dried (Na₂SO₄), and concentrated. Purification of the resulting residueby flash chromatography (SiO₂, 0-50% EtOAc in heptane) provided3-(4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile(2.47 g, 5.2 mmol, 99% yield) as a foamy off-white solid: LCMS (m/z)477.1 (MH⁺), t_(R)=0.98 minute.

Step 2. Preparation of3-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile(I-3b)

To a 200 mL round-bottom flask containing3-(4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile(2.46 g, 5.2 mmol) were added 2-propanol (10 mL) and PPTS (1.94 g, 7.7mmol). The reaction was heated to 90° C. in an oil bath for 3 hours,LCMS indicated 90% conversion. Additional pyridine (100 μL) and thereaction was maintained at 90° C. for another 5 hours. The reaction wasallowed to cool to room temperature and to an yellow gum. Added water(100 mL), adjusted to pH 7 with saturated aqueous NaHCO₃ solution, andextracted with EtOAc (2×100 mL). Combined EtOAc, washed with saturatedNaHCO₃ (1×100 mL), brine (1×100 mL), dried (Na₂SO₄), filtered, andconcentrated to obtain tacky yellow solids. The residue was trituratedin EtOAc-Et₂O (1 mL, 10 mL) to furnish3-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile(1.50 g, 4.10 mmol, 95% purity by LCMS) as off-white solids: LCMS (m/z)347.0 (MH⁺), t_(R)=0.59 minute; ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J=6.3Hz, 1H), 7.54 (d, J=6.3 Hz, 1H), 3.88 (t, J=6.3 Hz, 2H), 2.75 (t, J=6.5Hz, 2H), 1.47 (s, 3H), 1.22 (m, 2H), 0.84 (m, 2H).

Preparation of intermediate (S)-methyl1-(4-(4-bromo-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(I-4a)

Step 1. Preparation of 2-cyclobutyl-1H-imidazole

Pyridinium chlorochromate (PCC, 28.3 g, 131.0 mmol) was added tocyclobutanemethanol (10.3 mL, 109.0 mmol) in THF (90 mL). The thick,black reaction mixture was stirred at room temperature for 2 hours. Thereaction was filtered through Celite, and the filter pad was washed withTHF (15 mL). MeOH, glyoxal and ammonium hydroxide added sequentially tothe filtrate, and the reaction was stirred at room temperatureovernight. The reaction mixture was concentrated until what remained wasthe water layer which contained solids. The solids were filtered andwashed with water (10 mL). The tan solids were air dried and then driedunder high vacuum to give the product as a light brown solid (7.15 g).The aqueous filtrate was extracted with EtOAc (3×500 mL). The organiclayers were combined, dried (Na₂SO₄) and concentrated to give additionalproduct as a brown solid (2.85 g) which was used without furtherpurification: LCMS (m/z) 123.0 (MH⁺), t_(R)=0.28 minute.

Step 2. Preparation of 4,5-dibromo-2-cyclobutyl-1H-imidazole

To a mixture of 2-cyclobutyl-1H-imidazole (10.0 g, 82.0 mmol) and K₂CO₃(28.32 g, 205.0 mmol) in THF (150 mL) at room temperature was added NBS(29.14 g, 164 mmol) portionwise. The reaction mixture became warm so adry ice/acetone bath was used to cool the reaction during the addition.The resultant mixture was allowed to warm to room temperature andstirred for 3.5 hours. The reaction mixture was then diluted with EtOAc,washed sequentially with aqueous 50% Na₂S₂O₃ solution (2×), water,brine, dried (Na₂SO₄) and concentrated to a dark brown solid.Purification by flash chromatography (SiO₂, EtOAc in heptanes) gave4,5-dibromo-2-cyclobutyl-1H-imidazole as a white solid (1.76 g, ˜40purity): LCMS (m/z) 278.8 (MH⁺), t_(R)=0.56 minute.

Step 3. Preparation of 4,5-dibromo-2-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

A 250 mL round-bottom flask was purged with nitrogen and charged withNaH (95%, 0.2 g, 8.3 mmol). THF (10 mL) added, and the mixture cooled to0° C. After 5 minutes, a solution of4,5-dibromo-2-cyclobutyl-1H-imidazole (1.76 g, 6.29 mmol, ˜40% purity)in THF (20 mL) was added dropwise from an addition funnel over 5minutes. The reaction was stirred at 0° C. for 35 minutes and SEMCl (1.8mL, 10.2 mmol) was then added dropwise over 2 minutes. After 5 minutes,ice bath was removed, and the reaction stirred at room temperature for 4hours. LCMS indicated complete reaction. The reaction was then carefullyquenched with water (1.5 mL). Heptane (250 mL) was added and organiclayer was washed with water (200 mL). The aqueous layer was extractedwith heptane (100 mL), and the combined organic layers were washed withwater and brine, dried (Na₂SO₄), and concentrated to give 2.14 g ofcrude material. The crude material was purified by flash chromatography(SiO₂; EtOAc in heptane) to afford4,5-dibromo-2-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(0.43 g) as a yellow oil: LCMS (m/z) 408.9 (MH⁺), t_(R)=1.25 minutes.

Step 4. Preparation of4-(4-bromo-2-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine

To a solution of4,5-dibromo-2-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(0.43 g, 1.0 mmol) in THF (5 mL) at −78° C. under nitrogen was addedn-BuLi (2.0 M in pentane, 0.68 mL, 1.36 mmol), dropwise over 5 minutes.After 40 minutes, a solution of 2-chloropyrimidine (0.17 g, 1.47 mmol)in THF (5 mL) was added dropwise over one minute. The reaction wasstirred at −78° C. for 1 hour and LCMS indicated complete reaction. Thereaction was slowly quenched with 1:1 water-THF solution (50 mL) from anaddition funnel, keeping the temperature between −40° C. and −35° C.After 15 minutes of stirring, a solution of DDQ (0.36 g, 1.61 mmol) inTHF (20 mL) was added slowly, and the mixture was stirred for 15 minutesunder ice water cooling. Aqueous 2.0 N NaOH solution (12 mL) was thenadded followed by 1:1 water-THF solution (12 mL). The resulting mixturewas partitioned with EtOAc and the layers separated. The organic layerwas washed with water (2×), brine (2×), dried (Na₂SO₄), and concentratedto give a brown oil (0.45 g) as4-(4-bromo-2-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidinewhich was carried forward without further purification: LCMS (m/z) 443.1(MH⁺), t_(R)=1.27 minutes.

Step 5. Preparation of (S)-tert-butyl1-(4-(4-bromo-2-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate

A mixture of4-(4-bromo-2-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine(0.45 g, 1.01 mmol), (S)-tert-butyl 1-aminopropan-2-ylcarbamate (0.41 g,2.35 mmol) and diisopropyl ethylamine (0.55 mL, 3.15 mmol) in dry ACN (5mL) was stirred at 80° C. for 36 hours. The reaction mixture was allowedto cool to room temperature and diluted with EtOAc, washed with water(2×), brine, dried (Na₂SO₄), and concentrated to give a yellow oil (4.68g). The crude material was purified by flash chromatography (SiO₂, 0-60%EtOAc in heptane) to provide (S)-tert-butyl1-(4-(4-bromo-2-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(0.27 g, 5.5 mmol) as a white foam: LCMS (m/z) 581.2 (MH⁺), t_(R)=1.10minutes.

Step 6. Preparation of(S)—N1-(4-(4-bromo-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine

A mixture of ((S)-tert-butyl1-(4-(4-bromo-2-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(0.27 g, 0.47 mmol) in concentrated HCl (0.14 mL) and MeOH (4 mL) washeated to 80° C. for 5 hours. The reaction mixture was allowed to coolto room temperature and concentrated to a yellow solid to afford thecrude(S)—N1-(4-(4-bromo-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine(0.25 g) as the HCl salt which is used in next step withoutpurification: LCMS (m/z) 351.0 (MH⁺), t_(R)=0.45 minute.

Step 7. Preparation of (S)-methyl1-(4-(4-bromo-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(I-4a)

A solution ofS)—N1-(4-(4-bromo-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine(0.25 g, 0.72 mmol) in THF-water (1:1, 8 mL) was cooled to 0° C. andthen solid NaHCO₃ (0.10 g, 1.2 mmol) was added with concomitantfrothing. After 5 minutes, a THF solution of methyl chloroformate (0.1 Min THF, 4.3 mL, 0.43 mmol) was added dropwise to the mixture and thereaction was maintained overnight allowing the cooling bath to expire.LCMS indicate incomplete reaction and addition methyl chloroformatesolution and NaHCO₃ was added. After the reaction was deemed complete byLCMS, the reaction mixture was extracted with EtOAc. The organic phasewas washed with brine and dried (Na₂SO₄), and concentrated to give(S)-methyl1-(4-(4-bromo-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamateas a yellow solid (0.19 g): LCMS (m/z) 409.0 (MH⁺), t_(R)=0.63 minute.

Preparation of intermediate (S)-methyl1-(2-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)pyrimidin-4-ylamino)propan-2-ylcarbamate(I-5a)

Step 1. Preparation of2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

A dried 500 mL round bottom flask was charged with2,4,5-tribromoimidazole (20.0 g, 65.6 mmol) and anhydrous DMF (100 mL),the resulting solution was cooled to 0° C. To this cold solution wasadded NaH (60% in mineral oil, 2.80 g, 70.0 mmol) portionwise with gasevolution under control and an internal temperature maintained below 10°C. After addition, the cold bath was removed and the resulting mixturewas stirred at ambient temperature for 30 minutes. The reaction mixturewas cooled back to 0° C., and SEMCl (12.2 mL, 69.5 mmol) was added tothe reaction via syringe pump over 30 minutes. The reaction was stirredat 0° C. for an additional 30 minutes and at room temperature foranother 30 minutes. The reaction was deemed complete by LCMS and themixture was partitioned between EtOAc (150 mL) and water (300 mL), andthe layers separated. The organic phase was sequentially washed withdilute aqueous NaCl (5% w/w) twice, then brine (100 mL), dried (Na₂SO₄),concentrated and a light yellow solid was obtained. The crude materialwas recrystallized from hot petroleum ether (30 mL) and the solids wereharvested from the mother liquor at 0° C. The product was washed withcold petroleum ether (30 mL) and dried under vacuum to afford2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (26.3g, 92% yield): ¹H NMR (400 MHz, CDCl₃) δ 5.31 (s, 2H), 3.59 (t, J=7.2Hz, 2H), 0.92 (t, J=7.2 Hz, 2H), −0.01 (s, 9H).

Step 2. Preparation of4,5-dibromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

In a 200 mL round-bottomed flask,2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (10.2g, 23.45 mmol), 4-(trifluoromethyl)-phenylboronic acid (5.43 g, 28.6mmol), and aqueous 2.0 M Na₂CO₃ solution (20 mL, 40 mmol) in DME (70 mL)to give a colorless solution. The solution was sparged with Ar (3 X),Pd(PPh₃)₄ (400 mg, 0.646 mmol) was added, and the mixture was againsparged with Ar (3×). The reaction was heated to and maintained at 95°C. for 16 hours. LCMS analysis of an aliquot indicated 70% conversion.Additional 4-(trifluoromethyl)phenylboronic acid (2 g, 10.5 mmol) wasadded and the reaction mixture was sparged with Ar (3×). The reactionwas stirred under Ar at 95° C. for another 24 hours. LCMS analysisindicated near complete conversion. The reaction was allowed to cool toroom temperature and the reaction mixture partitioned upon standing. Thelayers were separated and the aqueous phase was extracted with EtOAc(2×20 mL). The organic layers were combined dried (Na₂SO₄), andconcentrated. The resulting residue was purified by flash chromatography(SiO₂, 0-50% EtOAc in hexanes) to furnish 9.87 g of4,5-dibromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole:LCMS (m/z) 498.9 (MH⁺), t_(R)=1.33 minutes; NMR δ 7.98 (d, J=9.0 Hz,2H), 7.72 (d, J=9.0 Hz, 2H), 5.32 (s, 2H), 3.74 (t, J=7.2 Hz, 2H), 0.99(t, J=7.2 Hz, 2H), 0.03 (s, 9H).

Step 3. Preparation of4-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine

A solution of4,5-dibromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(1.0 g, 2.0 mmol) in dry THF (10 mL) was cooled to −78° C. under Argon.n-BuLi (1.0 mL, 2.5 M in hexane, 2.5 mmol) was added dropwise,afterwards the reaction was maintained below −70° C. for an additional45 minutes. A solution of 2-chloropyrimidine (0.29 g, 2.5 mmol) in dryTHF (2 mL) was added dropwise at −78° C. After addition, the reactionwas allowed to warm to −40° C. over 25 minutes and maintained at −40° C.for 20 minutes. The reaction was then warmed to −5° C. in a brine-icebath, quenched with water (30 mL), and stirred at room temperature for30 minutes. The reaction mixture was concentrated and partitionedbetween EtOAc and water. The organic phase was separated, dried(Na₂SO₄), and concentrated. The resulting residue was further purifiedby flash chromatography (SiO₂, 0-20% EtOAc in hexanes) to afford 1.1 g(2.05 mmol, 82%) of6-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazol-5-yl)-2-chloro-1,6-dihydropyrimidine.A solution of6-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloro-1,6-dihydropyrimidine(410 mg, 0.8 mmol) in EtOAc (20 mL) was treated with MnO₂ (920 mg, 10.6mmol) and the resulting reaction mixture was heated to and maintained atreflux for 18 hours. The reaction was allowed to cool to roomtemperature and was then filtered through Celite. The filter cake waswashed with EtOAc (2×20 mL) and the combined filtrates were concentratedto give 400 mg (0.75 mmol, 98%) of4-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine:¹H NMR (400 MHz, CDCl₃) δ 8.71 (d, J=5.4 Hz, 1H), 8.02 (d, J=5.4 Hz,1H), 7.96 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.1 Hz, 2H), 5.77 (s, 2H), 3.49(t, J=7.5 Hz, 2H), 0.83 (t, J=7.5 Hz, 2H), 0.01 (s, 9H).

Step 3. Preparation of (S)-tert-butyl1-(2-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-4-ylamino)propan-2-ylcarbamate:

A solution of4-(4-bromo-2-(4-trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine(4.1 g, 7.7 mmol) in dry NMP (10 mL) was treated with(S)-tert-butyl-1-aminopropan-2-ylcarbamate (1.9 g, 11.0 mmol), followedby Na₂CO₃ (0.82 g, 7.7 mmol). The resulting mixture was heated to 80° C.for 4 hours whereupon the reaction was deemed complete by LCMS, andallowed to cool to room temperature. Water was added and the resultingsuspension was compacted by centrifugation. The filtrate was decanted,the remaining solids were washed with water, and dried under vacuum toprovide 4.6 g (6.9 mmol, 90%) as (S)-tert-butyl1-(2-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-4-ylamino)propan-2-ylcarbamate,which was carried forward without further purification: LCMS (m/z) 671.1(MH⁺), t_(R)=1.21 minutes.

Step 4. Preparation of(S)—N1-(4-(4-Bromo-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-propane-1,2-diamine

The mixture of (S)-tert-butyl1-(2-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-4-ylamino)propan-2-ylcarbamate(0.14 g, 0.21 mmol) in concentrated HCl (0.24 mL) and MeOH (5 mL) washeated at 80° C. for 3 hours, then stirred at room temperatureovernight. The reaction mixture was concentrated to a yellow solid toafford crude(S)—N1-(2-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)pyrimidin-4-yl)propane-1,2-diamine(0.12 g) as the HCl salt, which is used in next step withoutpurification: LCMS (m/z) 441.0 (MH⁺), t_(R)=0.68 minute.

Step 5. Preparation of (S)-methyl1-(2-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)pyrimidin-4-ylamino)propan-2-ylcarbamate(I-5a)

A solution of(S)—N1-(4-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine(0.12 g, 0.27 mmol) in THF (6 mL) and water (4 mL) was cooled to 0° C.and then NaHCO₃ (0.12 g, 1.4 mmol) was added. After 5 minutes, asolution of methyl chloroformate (0.12 M in THF, 2 mL, 2.4 mmol) wasadded dropwise to the reaction mixture. Over 2 hours, the reactionwarmed to room temperature and was extracted with EtOAc. The organicphase was washed with brine and dried (Na₂SO₄), and concentrated to give(S)-methyl1-(2-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)pyrimidin-4-ylamino)propan-2-ylcarbamateas a yellow solid (0.10 g): LCMS (m/z) 499.1 (MH⁺), t_(R)=0.89 minute.

Preparation of intermediate (S)-methyl1-(2-(4-bromo-2-(2,4-difluorophenyl)-1H-imidazol-5-yl)pyrimidin-4-ylamino)propan-2-ylcarbamate(I-6a)

(S)-methyl1-(2-(4-bromo-2-(2,4-difluorophenyl)-1H-imidazol-5-yl)pyrimidin-4-ylamino)propan-2-ylcarbamatewas prepared in a similar manner as described above:

LCMS (m/z) 467.1 (MH⁺), t_(R)=0.65 minute.

Example 1 Preparation of (S)-methyl1-(4-(4-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate,hydrogen chloride salt (1A)

To a solution of (S)-methyl1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(I-1b, 0.59 g, 1.5 mmol) in DME (15 mL) was added a solution of5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-5, (˜12 mL, 0.25 M solution in dioxane; 3.0 mmol) and aqueous Na₂CO₃solution (6 mL, 2.0 M, 12.0 mL). The resulting mixture was sparged withnitrogen, and Pd(PPh₃)₄ (87 mg, 0.075 mmol) was added. The reactionmixture was sealed and subjected to microwave irradiation at 120° C. forabout 20 minutes. The reaction was allowed to cool to room temperatureand partitioned upon standing. The layers were separated and the organicportion was concentrated, dissolved in EtOAc (150 mL), washed with water(50 mL), followed by extraction with aqueous 0.01 M HCl solution (2×100mL) and aqueous 0.02 M HCl solution (2×100 mL). The combined acidicaqueous portions were neutralized with saturated aqueous NaHCO₃solution, and extracted with EtOAc (2×225 mL). The combined organicportions were washed with brine, dried (Na₂SO₄), and concentrated toyield (S)-methyl1-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(530 mg) which was carried forward without further purification. LCMS(m/z) 460.2 (MH⁺), t_(R)=0.57 minute.

To a cooled solution of (S)-methyl1-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(530 mg, 1.2 mmol) in dry pyridine (1.2 mL) at 0-5° C., was slowly addedmethanesulfonyl chloride (71 μL, 0.92 mmol). After 2.5 hours, thereaction was allowed to warm to room temperature over 30 minutes afterwhich the reaction was partitioned between EtOAc (100 mL) and water (75mL). The layers were separated and the aqueous portion wasback-extracted with EtOAc (20 mL). The combined organics were thenextracted with 0.05 M NaOH (2×75 mL) and the combined basic aqueousextracts were neutralized with aqueous 0.1 M HCl solution and extractedwith EtOAc (2×125 mL). The organic portion was washed with brine, dried(Na₂SO₄) and concentrated to give a brown residue which was purified byreverse phase HPLC. The combined product fractions were concentrated invacuo. The remaining acidic aqueous solution was neutralized withsaturated aqueous NaHCO₃ solution and extracted with EtOAc (2×100 mL).The combined organic portion was then washed with brine, dried (Na₂SO₄),and concentrated. The resulting solid was then dissolved in a solutionof ACN and water and treated with one equivalent of 1.0 N aqueous HClsolution. Lyophilization afforded (S)-methyl1-(4-(4-(5-chloro-2-fluoro-3-(methylsulfonamido)-phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamateas the HCl salt (1A): LCMS (m/z): 538.1 (MH⁺), t_(R)=0.63 minute; ¹H NMR(400 MHz, CD₃CO₂D) δ ppm 8.27 (d, J=6.3 Hz, 1H), 7.78 (d, J=5.1, 1H),7.51 (d, J=2.4, 1H), 6.81 (d, J=5.9, 1H), 4.06 (d, J=4.7 Hz, 1H),3.74-3.87 (m, 1H), 3.71 (s, 3H), 3.2-3.28 (m, 1H), 3.17 (s, 3H), 2.60(br. s., 1H), 1.50 (br s, 2H), 1.34 (d, J=7.0 Hz, 2H), 1.21 (d, J=6.7Hz, 3H).

The compounds listed below were prepared using procedures analogous tothose described above for the preparation of Example 1A using theappropriate starting materials and isolated as either their free base orsalt form (generally, the trifluoroacetate or hydrogen chloride salt).

(S)-methyl1-(4-(2-cyclopropyl-4-(2-fluoro-5-methyl-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1B)

¹H NMR (300 MHz, CD₃CO₂D) δ 1.01-1.51 (m, 7H) 2.39 (s, 3H) 2.52 (m, 1H)3.09 (s, 3H) 3.17 (dd, J=12.9, 9.4 Hz, 1H) 3.71 (s, 3H) 3.80 (d, J=9.7Hz, 1H) 3.98-4.22 (m, 1H) 6.63 (d, J=5.6 Hz, 1H) 7.30 (d, J=4.4 Hz, 1H)7.53 (d, J=6.2 Hz, 1H) 8.17 (d, J=6.5 Hz, 1H). LCMS (m/z) (M+H)=518.2,Retention time (t_(R))=0.59 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(3-chloro-5-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1C)

LCMS (m/z) (M+H)=536.2, Retention time (tR)=0.50 minute.

(S)-methyl1-(4-(2-tert-butyl-4-(3-chloro-5-(trifluoroethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1D)

LCMS (m/z) (M+H)=590.3, Retention time (tR)=0.87 minute.

(S)-methyl1-(4-(2-tert-butyl-4-(3-chloro-5-(propylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1E)

LCMS (m/z) (M+H)=564.1, Retention time (tR)=0.72 minute.

(S)-methyl1-(4-(2-tert-butyl-4-(3-chloro-5-(cyclopropanesulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1F)

LCMS (m/z) (M+H)=562.1, Retention time (tR)=0.69 minute.

(S)-methyl1-(4-(2-tert-butyl-4-(3-chloro-5-(2-methylpropylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1G)

LCMS (m/z) (M+H)=578.1, Retention time (tR)=0.76 minute.

Methyl(2S)-1-(4-(2-tert-butyl-4-(3-chloro-5-(1-methylpropylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1H)

LCMS (m/z) (M+H)=578.2, Retention time (tR)=0.75 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(3-chloro-5-(ethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1I)

LCMS (m/z) (M+H)=550.1, Retention time (tR)=0.67 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(3-chloro-5-(1-methylethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1J)

¹H NMR (400 MHz, CD₃OD) δ 0.97-1.19 (m, 3H) 1.21-1.38 (m, 6H) 1.47 (brs, 9H) 2.92-3.21 (m, 2H) 3.60 (br s, 3H) 3.75-4.13 (m, 2H) 6.39-6.77 (m,1H) 7.27 (m, 3H) 7.90-8.34 (m, 1H). LCMS (m/z) (M+H)=564.2, Retentiontime (t_(R))=0.73 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(3-methoxy-4-methyl-5-(1-methylethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1K)

LCMS (m/z) (M+H)=574.2, Retention time (tR)=0.68 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(3-(cyclopropanesulfonamido)-5-methoxy-4-methylphenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1L)

LCMS (m/z) (M+H)=572.2, Retention time (tR)=0.66 minute.

(S)-Methyl1-(4-(4-(3-chloro-5-(1-methylethylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1M)

¹H NMR (400 MHz, CD₃OD) δ 1.03-1.59 (m, 13H) 2.37-2.70 (m, 1H) 3.30 (m,6H) 3.83-4.04 (m, 1H) 6.31-6.85 (m, 1H) 7.21-7.50 (m, 3H) 8.00-8.37 (m,1H). LCMS (m/z) (M+H)=548.3, Retention time (t_(R))=0.66 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(5-chloro-3-(cyclopropanesulfonamido)-2-methylphenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1N)

LCMS (m/z) (M+H)=576.1, Retention time (t_(R))=0.68 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(5-chloro-2-methyl-3-(1-methylethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1O)

LCMS (m/z) (M+H)=578.2, Retention time (t_(R))=0.7 minute.

(S)-Methyl1-(4-(2-tert-butyl-5-(3-(difluoromethoxy)-5-(1-methylethylsulfonamido)phenyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1P)

LCMS (m/z) (M+H)=596.2, Retention time (t_(R))=0.71 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(3-methyl-5-(1-methylethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1Q)

¹H NMR (300 MHz, CD₃OD) δ 1.02-1.23 (m, 3H) 1.25-1.40 (m, 6H) 1.59 (s,9H) 2.33-2.47 (m, 3H) 3.18-3.38 (m, 2H) 3.56-3.72 (m, 4H) 3.78-4.03 (m,1H) 6.61-6.84 (m, 1H) 7.12-7.19 (m, 1H) 7.19-7.26 (m, 1H) 7.26-7.34 (m,1H) 7.99-8.33 (m, 1H). LCMS (m/z) (M+H)=544.4, Retention time(t_(R))=0.65 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1R)

¹H NMR (400 MHz, CD₃OD) δ 1.11 (br s, 3H) 1.49-1.69 (s, 9H) 3.02 (s, 3H)3.35-3.54 (m, 1H) 3.62 (s, 3H) 3.88 (m, 1H) 6.73 (br s, 1H) 7.32-7.44(m, 3H) 7.49 (m, 1H) 7.55 (m, 1H) 8.17 (br s, 1H). LCMS (m/z)(M+H)=502.2, Retention time (t_(R))=0.57 minute.

(S)-Methyl1-(4-(4-(3-chloro-5-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1S)

LCMS (m/z) (M+H)=520, Retention time (t_(R))=0.59 minute.

(S)-Methyl1-(4-(4-(2-chloro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1T)

1H NMR (400 MHz, CD₃CO₂D) δ 1.21 (d, J=6.7 Hz, 3H) 1.35 (app d, J=7.8Hz, 2H) 1.52 (br s, 2H) 2.62 (br s, 1H) 3.12 (s, 3H) 3.18 (m, 1H) 3.72(s, 3H) 3.79 (m, 1H) 4.09 (br s, 1H) 6.46 (d, J=5.9 Hz, 1H) 7.46-7.59(m, 2H) 7.86 (d, J=7.8 Hz, 1H) 8.18 (d, J=5.9 Hz, 1H). LCMS (m/z)(M+H)=520.2, Retention time (t_(R))=0.53 minute.

(S)-Methyl1-(4-(2-cyclopropyl-4-(2-fluoro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1U)

¹H NMR (400 MHz, CD₃CO₂D) δ 1.21 (d, J=6.7 Hz, 3H) 1.36 (d, J=6.3 Hz,2H) 1.54 (br s, 2H) 2.63 (d, J=4.3 Hz, 1H) 3.13 (s, 3H) 3.20 (m, 1H)3.72 (s, 3H) 3.81 (d, J=10.6 Hz, 1H) 4.07 (d, J=3.5 Hz, 1H) 6.71 (d,J=5.9 Hz, 1H) 7.39 (m, 1H) 7.53 (m, 1H) 7.78 (m, 1H) 8.23 (d, J=6.3 Hz,1H). LCMS (m/z) (M+H)=504, Retention time (t_(R))=0.52 minute.

Methyl(2S)-1-(4-(2-cyclopropyl-4-(2,5-difluoro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1V)

¹H NMR (400 MHz, CD₃CO₂D) δ 1.11-1.36 (m, 7H) 2.39-2.54 (m, 1H)3.07-3.29 (m, 4H) 3.60-3.85 (m, 4H) 4.06 (m, 1H) 6.3 (d, J=6.26 Hz, 1H)7.19 (m, 1H) 7.51 (m, 1H) 8.19 (d, J=6.3 Hz, 1H). LCMS (m/z)(M+H)=522.1, Retention time (t_(R))=0.57 minute.

(S)-Methyl1-(4-(5-(5-chloro-2-fluoro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1W)

LCMS (m/z) (M+H)=566.2, Retention time (t_(R))=0.7 minute.

(S)-Methyl1-(4-(2-cyclopropyl-4-(2,5-dichloro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1X)

¹H NMR 300 MHz, CD₃CO₂D) δ 1.20 (app d, J=6.7 Hz, 5H) 1.31 (br s, 2H)2.42-2.53 (m, 1H) 3.13 (s, 3H) 3.15-3.24 (m, 1H), 3.71 (s, 3H) 3.74-3.77(m, 1H) 4.08 (br s, 1H) 6.45 (d, J=6.3 Hz, 1H) 7.47 (app d, J=1.6 Hz,1H) 7.83 (d, J=2.0 Hz, 1H) 8.17 (d, J=6.7 Hz, 1H). LCMS (m/z)(M+H)=554.1, Retention time (t_(R))=0.62 minute.

(S)-Methyl1-(4-(5-(5-chloro-3-(cyclopropanesulfonamido)-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1Y)

LCMS (m/z) (M+H)=564.1, Retention time (t_(R))=0.68 minute.

(S)-Methyl1-(4-(5-(5-chloro-3-(ethylsulfonamido)-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1Z)

LCMS (m/z) (M+H)=552.1, Retention time (t_(R))=0.66 minute.

(S)-Methyl1-(4-(5-(5-chloro-2-fluoro-3-(3,3,3-trifluoropropylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AA)

LCMS (m/z) (M+H)=620.1, Retention time (t_(R))=0.76 minute.

(S)-Methyl1-(4-(4-(2-chloro-5-methyl-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AB)

¹H NMR (400 MHz, CD₃CO₂D) δ 1.13-1.47 (m, 7H) 2.41 (s, 3H) 2.46-2.55 (m,1H) 3.08 (s, 3H) 3.17 (dd, J=12.7, 9.6 Hz, 1H) 3.63-3.85 (m, 4H)4.02-4.18 (m, 1H) 6.41 (d, J=6.3 Hz, 1H) 7.30 (br s, 1H) 7.64 (s, 1H)8.14 (d, J=6.3 Hz, 1H). LCMS (m/z) (M+H)=534.4, Retention time(t_(R))=0.55 minute.

(S)-Methyl1-(4-(5-(5-chloro-3-(cyclopropylmethylsulfonamido)-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AC)

LCMS (m/z) (M+H)=578.2, Retention time (t_(R))=0.66 minute.

(S)-Methyl1-(4-(4-(2-chloro-3-(ethylsulfonamido)-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AD)

¹H NMR (400 MHz, CD₃CO₂D) δ 1.20 (d, J=7.0 Hz, 7H) 1.33-1.40 (m, 3H)2.41-2.55 (m, 1H) 3.13-3.33 (m, 3H) 3.71 (s, 4H) 4.03-4.17 (m, 1H)6.35-6.45 (m, 1H) 7.16-7.26 (m, 1H) 7.61-7.71 (m, 1H) 8.12-8.24 (m, 1H).LCMS (m/z) (M+H)=552.1, Retention time (t_(R))=0.59 minute.

(S)-Methyl1-(4-(4-(2-chloro-3-(cyclopropanesulfonamido)-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AE)

¹H NMR (400 MHz, CD₃CO₂D) δ 0.99-1.06 (m, 2H) 1.10-1.17 (m, 2H)1.17-1.26 (m, 4H) 1.27-1.38 (m, 3H) 2.42-2.54 (m, 1H) 2.64-2.75 (m, 1H)3.12-3.25 (m, 1H) 3.72 (s, 4H) 4.03-4.17 (m, 1H) 6.33-6.44 (m, 1H)7.19-7.28 (m, 1H) 7.59-7.69 (m, 1H) 8.13-8.20 (m, 1H). LCMS (m/z)(M+H)=564.2, Retention time (t_(R))=0.61 minute.

Methyl(2S)-1-(4-(4-(2-chloro-6-fluoro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AF)

LCMS (m/z) (M+H)=566.2, Retention time (t_(R))=0.618 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AG)

LCMS (m/z) (M+H)=554.1, Retention time (t_(R))=0.63 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(2-chloro-5-fluoro-3-(propylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AH)

LCMS (m/z) (M+H)=582.2, Retention time (t_(R))=0.70 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AI)

LCMS (m/z) (M+H)=554.2, Retention time (t_(R))=0.67 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(5-chloro-3-(ethylsulfonamido)-2-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AJ)

LCMS (m/z) (M+H)=568.2, Retention time (t_(R))=0.70 minute.

N-(2-Chloro-3-(5-(2-(2-cyanopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)phenyl)methanesulfonamide(1AK)

LCMS (m/z) (M+H)=472.1, Retention time (t_(R))=0.51 minute.

(S)-Methyl1-(4-(5-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AL)

LCMS (m/z) (M+H)=552.2, Retention time (t_(R))=0.65 minute.

(S)-Methyl1-(4-(5-(2-fluoro-5-methyl-3-(methylsulfonamido)phenyl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AM)

LCMS (m/z) (M+H)=532.2, Retention time (t_(R))=0.60 minute.

N-(2-Chloro-3-(2-cyclopropyl-5-(2-(propylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)propane-1-sulfonamide(1AN)

LCMS (m/z) (M+H)=493.0, Retention time (t_(R))=0.70 minute.

(S)-Methyl1-(4-(5-(2-chloro-3-(methylsulfonamido)phenyl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AO)

LCMS (m/z) (M+H)=534.2, Retention time (t_(R))=0.57 minute.

N-(2-Chloro-3-(2-cyclopropyl-5-(2-(propylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide(1AP)

LCMS (m/z) (M+H)=465.0, Retention time (t_(R))=0.59 minute.

N-(2-Chloro-3-(2-cyclopropyl-5-(2-(ethylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide(1AQ)

LCMS (m/z) (M+H)=451.0, Retention time (t_(R))=0.53 minute.

N-(2-Chloro-3-(2-cyclopropyl-5-(2-(isobutylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide(1AR)

LCMS (m/z) (M+H)=479.1, Retention time (t_(R))=0.63 minute.

N-(2-Chloro-3-(2-cyclopropyl-5-(2-(ethylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)propane-1-sulfonamide(1AS)

LCMS (m/z) (M+H)=479.1, Retention time (t_(R))=0.63 minute.

N-(2-Chloro-3-(2-cyclopropyl-5-(2-(isopropylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide(1AT)

LCMS (m/z) (M+H)=465.1, Retention time (t_(R))=0.57 minute.

N-(2-Chloro-3-(2-cyclopropyl-5-(2-(isopropylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)propane-1-sulfonamide(1AU)

LCMS (m/z) (M+H)=493.1, Retention time (t_(R))=0.67 minute.

(R)-Methyl1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AV)

¹H NMR (400 MHz, CD₃CO₂D) δ 1.20 (d, J=6.3 Hz, 5H) 1.25-1.40 (m, 2H)2.30-2.57 (m, 1H) 3.15 (s, 3H) 3.18-3.36 (m, 1H) 3.71 (s, 4H) 3.93-4.21(m, 1H) 6.31-6.61 (m, 1H) 7.21 (dd, J=7.8, 2.7 Hz, 1H) 7.53-7.68 (m, 1H)8.03-8.23 (m, 1H).

LCMS (m/z) (M+H)=538.1, Retention time (t_(R))=0.57 minute.

(S)-Methyl1-(4-(5-(5-chloro-2-fluoro-3-(4-fluorophenylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AW)

LCMS (m/z) (M+H)=618.2, Retention time (t_(R))=0.76 minute.

(S)-Methyl1-(4-(5-(5-chloro-2-fluoro-3-(3-fluorophenylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1AX)

LCMS (m/z) (M+H)=618.2, Retention time (t_(R))=0.75 minute.

N-(2-Chloro-3-(5-(2-(2-cyanoethylamino)pyrimidin-4-yl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide(1AY)

¹H NMR (400 MHz, CDCl₃) δ 0.87-0.94 (m, 2H) 1.26-1.34 (m, 2H) 1.60 (s,3H) 2.73 (t, J=6.1 Hz, 2H) 3.07 (s, 3H) 3.79 (t, J=6.1 Hz, 2H) 5.59 (brs, 1H) 6.13 (d, J=5.5 Hz, 1H) 7.05 (m, 1H) 7.53 (m, 1H) 8.06 (d, J=5.5Hz, 1H) 10.05 (br s, 1H). LCMS (m/z) (M+H)=490.0, Retention time(t_(R))=0.55 minute.

methylcyclopropyl)-1H-imidazol-4-yl)-5-methylphenyl)methanesulfonamide(1AZ)

¹H NMR (400 MHz, CDCl₃) δ 0.85-0.94 (m, 2H) 1.26-1.35 (m, 2H) 1.60 (s,3H) 1.63 (br s, 1H) 2.38 (s, 3H) 2.73 (t, J=5.9 Hz, 2H) 3.02 (s, 3H)3.78 (d, J=5.9 Hz, 2H) 5.65 (br s, 1H) 6.11 (d, J=5.5 Hz, 1H) 7.14 (s,1H) 7.55 (s, 1H) 8.01 (d, J=5.1 Hz, 1H) 10.02 (br s, 1H). LCMS (m/z)(M+H)=486.1, Retention time (t_(R))=0.55 minute.

N-(3-(5-(2-(2-Cyanoethylamino)pyrimidin-4-yl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)-2-fluoro-5-methylphenyl)methanesulfonamide(1BA):

LCMS (m/z) (M+H)=470.1, Retention time (t_(R))=0.55 minute.

N-(5-Chloro-3-(5-(2-(2-cyanoethylamino)pyrimidin-4-yl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)-2-fluorophenyl)methanesulfonamide(1BB)

LCMS (m/z) (M+H)=490.2, Retention time (t_(R))=0.62 minute.

N-(2-Chloro-3-(5-(2-(2-cyanoethylamino)pyrimidin-4-yl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)phenyl)methanesulfonamide(1BC)

¹H NMR (400 MHz, CDCl₃) δ 0.81-1.01 (m, 2H) 1.28-1.39 (m, 2H) 1.61 (s,3H) 2.11-2.44 (m, 1H) 2.70 (br s, 2H) 3.05 (s, 3H) 3.75 (br s, 2H) 5.83(br s, 1H) 6.14 (br s, 1H) 7.31 (d, J=7.4 Hz, 1H) 7.40 (m, 1H) 7.74 (d,J=7.8 Hz, 1H) 8.02 (d, J=3.9 Hz, 1H) 9.82-10.39 (br s, 1H). LCMS (m/z)(M+H)=472.2, Retention time (t_(R))=0.53 minute.

N-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butyl-1H-imidazol-4-yl)-5-chloro-2-fluorophenyl)methanesulfonamide(1BD)

¹H NMR (400 MHz, CDCl₃) δ 1.50 (s, 9H) 3.15 (s, 3H) 6.66-6.81 (m, 1H)7.35-7.42 (m, 1H) 7.60-7.69 (m, 1H) 7.93-8.02 (m, 1H). LCMS (m/z)(M+H)=439.0, Retention time (t_(R))=0.57 minute.

N-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butyl-1H-imidazol-4-yl)-5-chloro-2-fluorophenyl)-2,6-difluorobenzenesulfonamide(1BE)

1H NMR (400 MHz, CDCl₃) δ 1.50 (s, 9H) 6.56-6.66 (m, 1H) 7.06 (m, 2H)7.31-7.37 (m, 1H) 7.38-7.48 (m, 1H) 7.50-7.62 (m, 1H) 7.63-7.68 (m, 1H)7.90-7.96 (m, 1H).

LCMS (m/z) (M+H)=537.1, Retention time (t_(R))=0.70 minute.

N-(3-(5-(2-Aminopyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-5-chloro-2-fluorophenyl)-2,6-difluorobenzenesulfonamide(1BF)

¹H NMR (400 MHz, CD₃CO₂D) δ 1.05-1.20 (m, 4H), 2.16-2.28 (m, 1H)6.61-6.70 (m, 1H) 6.91-7.04 (m, 2H) 7.28-7.36 (m, 1H) 7.44-7.54 (m, 1H)7.54-7.62 (m, 1H) 8.08-8.20 (m, 1H). LCMS (m/z) (M+H)=521.1, Retentiontime (t_(R))=0.65 minute.

N-(3-(5-(2-Aminopyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-5-chloro-2-fluorophenyl)methanesulfonamide(1BG)

¹H NMR (400 MHz, CD₃CO₂D) δ 1.20-1.38 (m, 4H) 2.32-2.44 (m, 1H) 3.14 (s,3H) 6.90-6.99 (m, 1H) 7.42-7.52 (m, 1H) 7.67-7.77 (m, 1H) 8.25-8.36 (m,1H). LCMS (m/z) (M+H)=423.1, Retention time (t_(R))=0.51 minute.

N-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butyl-1H-imidazol-4-yl)-5-chloro-2-fluorophenyl)propane-1-sulfonamide(1BH)

¹H NMR (400 MHz, CD₃CO₂D) δ 0.96-1.08 (m, 3H) 1.55 (s, 9H) 1.78-1.92 (m,2H) 3.16-3.27 (m, 2H) 6.99-7.07 (m, 1H) 7.44-7.52 (m, 1H) 7.70-7.79 (m,1H) 8.30-8.40 (m, 1H). LCMS (m/z) (M+H)=467.1, Retention time(t_(R))=0.65 minute.

(S)-Methyl1-(4-(4-(2-chloro-3-(2,6-difluorophenylsulfonamido)-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1BI)

¹H NMR (400 MHz, CD₃CO₂D) δ 1.19 (d, J=7.0 Hz, 3H) 1.22-1.28 (m, 2H)1.33 (br s, 2H) 2.41-2.57 (m, 1H) 3.16 (m, 1H) 3.70 (s, 3H) 3.76 (m, 1H)3.99-4.18 (m, 1H) 6.26 (d, J=6.3 Hz, 1H) 7.12 (m, 2H) 7.22 (dd, J=7.8,2.4 Hz, 1H) 7.56-7.76 (m, 2H) 8.15 (d, J=6.3 Hz, 1H). LCMS (m/z)(M+H)=636.1, Retention time (t_(R))=0.72 minute.

N-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butyl-1H-imidazol-4-yl)-2-chloro-5-fluorophenyl)methanesulfonamide(1BJ)

¹H NMR (400 MHz, CD₃CO₂D) δ 1.56 (s, 9H) 3.14 (s, 3H) 6.75-6.85 (m, 1H)7.24-7.33 (m, 1H) 7.57-7.68 (m, 1H) 8.22-8.32 (m, 1H). LCMS (m/z)(M+H)=439.0, Retention time (t_(R))=0.50 minute.

N-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butyl-1H-imidazol-4-yl)-2-chlorophenyl)-2,6-difluorobenzenesulfonamide(1BK)

¹H NMR (400 MHz, CD₃CO₂D) δ1.54 (s, 9H) 6.35-6.46 (m, 1H) 7.03-7.14 (m,2H) 7.48 (s, 2H) 7.56-7.69 (m, 1H) 7.78-7.88 (m, 1H) 8.11-8.22 (m, 1H).LCMS (m/z) (M+H)=519.0, Retention time (t_(R))=0.59 minute.

N-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butyl-1H-imidazol-4-yl)-2-chlorophenyl)methanesulfonamide(1BL)

¹H NMR (400 MHz, CD₃CO₂D) δ 1.57 (s, 9H) 3.10 (s, 3H) 6.58-6.69 (m, 1H)7.45-7.57 (m, 2H) 7.76-7.89 (m, 1H) 8.16-8.27 (m, 1H). LCMS (m/z)(M+H)=421.0, Retention time (t_(R))=0.43 minute.

(S)-Methyl1-(4-(4-(5-chloro-3-(3,5-difluorophenylsulfonamido)-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1BM)

LCMS (m/z) (M+H)=636.2, Retention time (t_(R))=0.81 minute.

(S)-Methyl1-(4-(4-(5-chloro-2-fluoro-3-(4-(trifluoromethyl)phenylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1BN)

LCMS (m/z) (M+H)=668.2, Retention time (t_(R))=0.85 minute.

(S)-Methyl1-(4-(2-cyclopropyl-4-(2-fluoro-5-methyl-3-(2,2,2-trifluoroethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1BO)

¹H NMR (400 MHz, CD₃CO₂D) δ 0.99-1.57 (m, 7H) 2.26-2.64 (m, 4H)3.03-3.29 (m, 1H) 3.56-3.90 (m, 4H) 4.07 (br s, 1H) 4.20 (m, 2H) 6.61(m, 1H) 7.34 (d, J=3.9 Hz, 1H) 7.53 (d, J=5.5 Hz, 1H) 8.15 (d, J=5.9 Hz,1H). LCMS (m/z) (M+H)=586.2, Retention time (t_(R))=0.67 minute.

N-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butyl-1H-imidazol-4-yl)-2-chloro-5-fluorophenyl)-2,6-difluorobenzenesulfonamide(1BP)

¹H NMR (400 MHz, CD₃CO₂D) δ 1.52 (s, 9H) 6.52-6.59 (m, 1H) 7.07-7.16 (m,2H) 7.22-7.29 (m, 1H) 7.59-7.70 (m, 2H) 8.20 (d, J=6.3 Hz, 1H). LCMS(m/z) (M+H)=537.0, Retention time (t_(R))=0.65 minute.

N-(3-(5-(2-Aminopyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chloro-5-fluorophenyl)methanesulfonamide(1BQ)

¹H NMR (400 MHz, CD₃CO₂D) δ 1.22-1.41 (m, 4H) 2.34-2.47 (m, 1H) 3.14 (s,3H) 6.64-6.74 (m, 1H) 7.22-7.31 (m, 1H) 7.57-7.70 (m, 1H) 8.22-8.34 (m,1H). LCMS (m/z) (M+H)=423.0, Retention time (t_(R))=0.43 minute.

N-(3-(5-(2-Aminopyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chloro-5-fluorophenyl)-2,6-difluorobenzenesulfonamide(1BR)

¹H NMR (400 MHz, CD₃CO₂D) δ 1.05-1.22 (m, 4H) 2.16-2.30 (m, 1H)6.27-6.38 (m, 1H) 6.92-7.03 (m, 2H) 7.05-7.14 (m, 1H) 7.45-7.57 (m, 2H)8.02-8.13 (m, 1H). LCMS (m/z) (M+H)=521.1, Retention time (t_(R))=0.59minute.

N-(3-(5-(2-Aminopyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chloro-5-fluorophenyl)propane-1-sulfonamide(1BS)

¹H NMR (400 MHz, CD₃CO₂D) δ 1.02 (s, 3H) 1.21-1.40 (m, 4H) 1.77-1.93 (m,2H) 2.32-2.48 (m, 1H) 3.17-3.29 (m, 2H) 6.62-6.71 (m, 1H) 7.17-7.28 (m,1H) 7.61-7.73 (m, 1H) 8.21-8.31 (m, 1H). LCMS (m/z) (M+H)=451.0,Retention time (t_(R))=0.56 minute.

(S)-Methyl1-(4-(4-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1BT)

LCMS (m/z) (M+H)=552.3, Retention time (t_(R))=0.66 minute.

(S)-Methyl1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1BU):

LCMS (m/z) (M+H)=552.2, Retention time (t_(R))=0.63 minute.

N-(2-Chloro-3-(2-cyclopropyl-5-(2-(methylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)-2,6-difluorobenzenesulfonamide(1BV):

¹H NMR (300 MHz, CD₃CO₂D) δ 1.07-1.09 (m, 4H) 2.17-2.21 (m, 1H) 2.49 (s,3H) 6.64 (m, 1H) 6.96-7.08 (m, 3H) 7.47-7.55 (m, 2H) 8.08-8.11 (d, 1H).LCMS (m/z) (M+H)=535.1, Retention time (t_(R))=0.64 minute.

N-(2-Chloro-3-(2-cyclopropyl-5-(2-(methylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide(1BW)

¹H NMR (300 MHz, CD₃CO₂D) δ 1.31 (br. s., 4H) 2.30-2.50 (m, 1H) 2.80 (brs, 3H) 3.15 (s, 3H) 6.84-6.98 (m, 1H) 7.20-7.35 (m, 1H) 7.63 (m, 1H)8.32 (br s, 1H). LCMS (m/z) (M+H)=437.1, Retention time (t_(R))=0.49minute.

N-(2-Chloro-3-(2-cyclopropyl-5-(2-(methylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)propane-1-sulfonamide(1BX)

¹H NMR (400 MHz, CD₃CO₂D) δ1.02 (t, J=7.4 Hz, 3H) 1.20 (br s, 4H)1.78-1.93 (m, 2H) 2.23-2.39 (m, 1H) 2.75 (s, 3H) 3.15-3.29 (m, 2H)6.72-6.86 (m, 1H) 7.12-7.25 (m, 1H) 7.54-7.67 (m, 1H) 8.17-8.28 (m, 1H).LCMS (m/z) (M+H)=465.2, Retention time (t_(R))=0.58 minute.

(S)-Methyl1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-(2,4-difluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1BY)

LCMS (m/z) (M+H)=610.0, Retention time (t_(R))=0.62 minute.

(S)-Methyl1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(1BZ)

LCMS (m/z) (M+H)=642.1, Retention time (t_(R))=0.82 minute.

Example 2 Preparation ofN-(5-chloro-3-(5-(2-(2-cyanoethylamino)pyrimidin-4-O-2-cyclopropyl-1H-imidazol-4-yl)-2-fluorophenyl)methanesulfonamide,free base and hydrogen chloride salt (2A-1 and 2A-2)

Two separate reaction vials were each charged with3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile(I-1c, ˜200 mg, 0.43 mmol), a solution of5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(0.2 M in dioxane, 8 mL, 1.6 mmol), DME (8 mL) and aqueous 2.0 M Na₂CO₃solution (2.3 mL, 4.6 mmol). The resulting mixture was sparged withArgon and Pd(PPh₃)₄ was added. The reaction vials were sealed andirradiated at 120° C. for 20 minutes in a microwave reactor. LCMSindicated near complete conversion. Additional5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(0.2 M in dioxane, 8 mL, 1.6 mmol) was added and the reaction wasirradiated at 120° C. for 7 minutes. The reactions were allowed to coolto room temperature which partitioned upon standing. The layers wereseparated and the organic portions of the two reactions were combinedand concentrated. The resulting residue was partitioned between EtOAc(200 mL) and water (20 mL). The layers were separated and the organicportion was washed with aqueous 0.1 N HCl solution (40 mL), brine, dried(Na₂SO₄), and concentrated to give3-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrileas a crude residue which was carried forward without furtherpurification: LCMS (m/z) 528.2 (MH⁺), t_(R)=0.90 minute.

To a solution of3-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile(0.58 g, 1.1 mmol) in EtOH (10 mL) was added concentrated HCl (1 mL).The resulting reaction was maintained at room temperature for 9 hoursafter which the reaction mixture was concentrated and partitionedbetween water (60 mL) and EtOAc (250 mL). The layers were separated andthe aqueous portion was neutralized with solid NaHCO₃, and thenextracted with EtOAc (200, 100 mL). The combined organic portions werethen extracted with 0.1 M aqueous HCl solution (2×100 mL). The combinedacidic aqueous extracts were neutralized with solid NaHCO₃ and extractedwith EtOAc (2×100 mL). The combined organic phases were washed withbrine, dried (Na₂SO₄), and then concentrated to furnish3-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile(328 mg) as an amber residue which was carried forward without furtherpurification: LCMS (m/z) 398.1 (MH⁺), t_(R)=0.55 minute.

To an ice-bath cooled solution of3-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile(328 mg, 0.82 mmol) in dry pyridine (1 mL) was slowly addedmethanesulfonyl chloride 100 μL, 1.3 mmol). After 6 hours allowing thecooling bath to expire, the reaction was partitioned between EtOAc (60mL) and water (30 mL). The layers were separated and the aqueous phasewas extracted with EtOAc (40 mL). The combined organic phases werewashed with brine, dried (Na₂SO₄) and concentrated to give 430 mg of areddish-brown residue which was purified by reverse phase HPLC. Thecombined product fractions were concentrated in vacuo and the remainingaqueous solution was neutralized with aqueous 2.0 M NaOH solution andextracted with EtOAc (3×75 mL). The combined organic phases were thenconcentrated and dissolved in DCM (150 mL) and extracted with aqueous0.1 M NaOH solution (2×125 mL). The combined aqueous extracts wereneutralized with aqueous 1.0 M HCl solution and then extracted with DCM(3×75 mL). The combined organic extracts were washed with brine, dried(Na₂SO₄), and concentrated. The resulting free base (2A-1) was convertedto the corresponding hydrogen chloride salt by dissolving inacetonitrile-water (7 mL) containing 1 equivalent of HCl and lyophilizedto yield 134 mg of the titled compound as the hydrochloride salt (2A-2):LCMS (m/z) 476.1 (MH⁺), retention time t_(R)=0.57 minute; ¹H NMR (400MHz, CD₃CO₂D) δ 8.34 (d, J=5.9 Hz, 1H), 7.64-7.90 (m, 1H), 7.31-7.59 (m,1H), 7.12 (d, J=4.3 Hz, 1H), 3.66 (t, J=6.1 Hz, 2H), 3.18 (s, 3H), 2.65(d, J=5.5 Hz, 2H), 2.50 (dd, J=8.2, 3.9 Hz, 1H), 1.04-1.68 (m, 5H).

The compounds listed below were prepared using procedures analogous tothose described above for the preparation of Example 2A using theappropriate starting materials and isolated as either their free base orsalt form (generally, the trifluoroacetate or hydrogen chloride salt).

(S)-Methyl1-(4-(2-tert-butyl-4-(3-(cyclopropanesulfonamido)-2-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(2B)

LCMS (m/z) (M+H)=546.2, Retention time (t_(R))=0.6 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(2-fluoro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(2C)

LCMS (m/z) (M+H)=520.1, Retention time (t_(R))=0.55 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(2-fluoro-3-(1-methylethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(2D)

LCMS (m/z) (M+H)=548.2, Retention time (t_(R))=0.62 minute.

N-(3-(5-(2-(2-Cyanoethylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-fluorophenyl)methanesulfonamide(2E)

¹H NMR (300 MHz, CD₃CO₂D) δ 1.10-1.36 (m, 4H) 2.26-2.38 (m, 1H) 2.58 (t,J=6.3 Hz, 2H) 3.12 (d, J=2.1 Hz, 3H) 3.58 (t, J=5.9 Hz, 2H) 6.92 (d,J=5.3 Hz, 1H) 7.35 (t, J=8.8 Hz, 1H) 7.45 (app t, J=6.9 Hz, 1H) 7.71(app t, J=7.8 Hz, 1H) 8.26 (dd, J=5.9, 2.1 Hz, 1H). LCMS (m/z)(M+H)=442.1, Retention time (t_(R))=0.47 minute.

Methyl (2S) 1 (4 (4 (2chloro-6-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(2F)

LCMS (m/z) (M+H)=538.1, Retention time (t_(R))=0.57 minute.

N-(2-Chloro-3-(5-(2-((1-cyanocyclopropyl)methylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)phenyl)methanesulfonamide(2G)

¹H NMR (300 MHz, CD₃OOD) δ 0.98-1.09 (m, 2H) 1.15-1.30 (m, 6H) 2.29-2.42(m, 1H) 3.10 (s, 3H) 3.40 (s, 2H) 6.79 (d, J=5.9 Hz, 1H) 7.47-7.58 (m,2H) 7.81 (dd, J=7.8, 1.9 Hz, 1H) 8.22 (d, J=6.2 Hz, 1H). LCMS (m/z)(M+H)=484.1, Retention time (t_(R))=0.52 minute.

N-(3-(5-(2-aminopyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chlorophenyl)-2,6-difluorobenzenesulfonamide(2H)

LCMS (m/z) (M+H)=503.1, Retention time (t_(R))=0.57 minute.

N-(2-Chloro-3-(2-cyclopropyl-5-(pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)-2,6-difluorobenzenesulfonamide(2I)

¹H NMR (300 MHz, CD₃CO₂D) δ 1.28-1.33 (m, 4H) 2.28-2.42 (m, 1H)7.08-7.14 (m, 3H) 7.26 (m, 1H) 7.66-7.70 (m, 2H) 8.69 (m, 1H) 9.10 (m,1H). LCMS (m/z) (M+H)=506, Retention time (t_(R))=0.63 minute.

N-(2-Chloro-3-(2-cyclopropyl-5-(pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide(2J)

¹H NMR (300 MHz, CD₃CO₂D) δ 1.31-1.55 (m, 4H) 2.40-2.60 (m, 1H) 3.15 (s,3H) 7.26-7.43 (m, 2H) 7.61-7.76 (m, 1H) 8.72-8.84 (m, 1H) 9.23 (s, 1H).LCMS (m/z) (M+H)=408.0, Retention time (t_(R))=0.48 minute.

N-(2-Chloro-3-(2-cyclopropyl-5-(pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)propane-1-sulfonamide(2K)

¹H NMR (300 MHz, CD₃CO₂D) δ 1.00-1.05 (t, 3H), 1.34-1.41 (m, 4H)1.81-1.89 (m, 2H), 2.40-2.60 (m, 1H) 3.20-3.26 (t, 2H) 7.26-7.33 (m, 2H)7.68-7.72 (m, 1H) 8.76-8.77 (m, 1H) 9.21 (s, 1H). LCMS (m/z)(M+H)=436.1, Retention time (t_(R))=0.58 minute.

Example 3 Preparation ofN-(3-(2-cyclopropyl-5-(2-(methylamino)pyrimidin-4-O-1H-imidazol-4-yl)-2-fluorophenyl)methanesulfonamide,free base (3A-1) and hydrogen chloride salt (3A-2)

To a solution of3-(5-(2-chloropyrimidin-4-yl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroaniline (I-1i, 81 mg, 0.15 mmol) indry NMP (2 mL) was added methylamine solution (2.0 M in THF, 0.38 ml,0.76 mmol). The reaction was then sealed and heated to and maintained at80° C. for 3 hours. LCMS indicated no conversion. After allowing to coolto room temperature, another solution of methylamine was added (2.0 M inMeOH) and the resulting reaction was heated to and maintained at 80° C.for 2 hours. LCMS indicated complete conversion. The reaction wasallowed to cool to room temperature and was diluted with saturatedaqueous NH₄Cl solution and extracted with EtOAc (2×). The combinedextracts were washed with brine, dried (Na₂SO₄), and concentrated togiveN-(3-(2-cyclopropyl-5-(2-(methylamino)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluorophenyl)methanesulfonamide(78 mg, 0.143 mmol, 95%) as a yellow residue which was carried forwardwithout further purification: LCMS (m/z) 533.2 (MH⁺), t_(R)=0.83 minute.

A solution ofN-(3-(2-cyclopropyl-5-(2-(methylamino)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluorophenyl)methanesulfonamide(78 mg, 0.14 mmol) in EtOH (2 mL) was treated with aqueous 6.0 N HClsolution and the resulting reaction was heated at 60° C. for 1 hour.LCMS indicated complete reaction, and the reaction was allowed to coolto room temperature. The volatiles were removed in vacuo, and theresulting residue was dissolved in DMSO and purified by reverse phaseHPLC. Product fractions were combined, neutralized with saturatedaqueous NaHCO₃ solution (pH=6), and extracted with DCM (2×). Thecombined organic portions were dried (Na₂SO₄), and concentrated. Theresulting free base (3A-1) was dissolved in ACN, treated with aqueous1.0 N HCl solution, frozen, and lyophilized to provideN-(3-(2-cyclopropyl-5-(2-(methylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-2-fluorophenyl)methanesulfonamide(23 mg) as the HCl salt (3A-2): LCMS (m/z) 402.9, (MH⁺), t_(R)=0.44minute; ¹H NMR (300 MHz, CD₃CO₂D) δ 1.26-1.38 (m, 2H) 1.37-1.52 (m, 2H)2.41-2.60 (m, 1H) 2.84 (br s, 3H) 3.12 (s, 3H) 7.03 (d, J=6.5 Hz, 1H)7.29-7.41 (m, 1H) 7.44-7.59 (m, 1H) 7.69-7.84 (m, 1H) 8.29 (d, J=6.5 Hz,1H).

The following compound was prepared using procedures analogous to thepreparation of Example 3A above using the appropriate startingmaterials.

(S)—N-(3-(2-cyclopropyl-5-(2-(2-hydroxypropylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-2-fluorophenyl)methanesulfonamide,hydrogen chloride salt (3B)

LCMS (m/z) 447.0 (MH⁺), t_(R)=0.44; ¹H NMR (300 MHz, CD₃CO₂D) δ 1.21 (d,J=5.9 Hz, 3H) 1.38-1.48 (m, 2H) 1.52 (m, 2H) 2.70 (br s, 1H) 3.14 (s,3H) 3.42-3.61 (m, 2H) 4.04 (br s, 1H) 7.14 (d, J=5.9 Hz, 1H) 7.34-7.47(m, 1H) 7.49-7.63 (m, 1H) 7.74-7.91 (m, 1H) 8.40 (d, J=6.5 Hz, 1H).

Example 4 Preparation of Methyl(2S)-1-(4-(2-cyclopropyl-4-(2,5-difluoro-3-(methylsulfonamido)-phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate,free base (4A-1), hydrochloride salt (4A-2) and trifluoroacetate salt(4A-3)

To a mixture of (S)-tert-butyl1-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (I-1a,256 mg, 0.45 mmol),N-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(SM-10, 292 mg, 0.81 mmol), aqueous 2.0 M Na₂CO₃ solution in DME (4 mL)was added PdCl₂(dppf)•DCM. The reaction vial was sealed and irradiatedat 120° C. for 10 minutes in a microwave reactor. LCMS indicatedcomplete conversion and the reaction was allowed to cool to roomtemperature. The reaction mixture was diluted with water and extractedwith EtOAc (2×). The combined organic portions were washed with water,brine, dried (Na₂SO₄), and concentrated to furnish a dark red oil.Purification by flash chromatography (SiO₂, 50-100% EtOAc in heptane)provided (S)-tert-butyl1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(4A-1: 116 mg, 0.14 mmol) as a yellow oil: LCMS (m/z) 720.3, (MH),t_(R)=1.03 minutes.

A solution of (S)-tert-butyl1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(116 mg, 0.14 mmol) in EtOH (2 mL) was treated with aqueous 6.0 N HClsolution (0.8 mL, 4.8 mmol) and the resulting reaction was heated to 60°C. for 30 minutes, then at room temperature for 40 minutes. The reactionwas allowed to cool to room temperature and the volatiles were removedin vacuo. Further drying under high vacuum afforded(S)—N-(3-(5-(2-(2-aminopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chlorophenyl)propane-1-sulfonamide(80 mg, 0.15 mmol) as the HCl salt (4A-2) which was used without furtherpurification: LCMS (m/z) 490.2 (MH⁺), t_(R)=0.48 minute.

To a mixture of(S)—N-(3-(5-(2-(2-aminopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chlorophenyl)propane-1-sulfonamidein THF-water (1:1, 2 mL) at 0° C. was added solid NaHCO₃ (137 mg, 1.6mmol) and the resulting mixture was stirred for 5 minutes. Methylchloroformate (14 μL, 0.18 mmol) was added and the reaction mixture wasstirred at 0° C. for 15 minutes. The reaction was diluted with water andextracted with EtOAc (2×). The combined organic portions were washedwith water, brine, dried (Na₂SO₄), and concentrated. The resultingresidue was dissolved in DMSO and purified by reverse phase HPLC.Product fractions were combined and lyophilized to give (S)-methyl1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(19.9 mg) as the TFA salt (4A-3): LCMS (m/z) 548.0 (MH⁺), t_(R)=0.61minute, ¹H NMR (400 MHz, CD₃OD) δ 1.04 (t, J=7.4 Hz, 3H) 1.14 (d, J=6.6Hz, 3H) 1.27 (t, J=4.5 Hz, 2H) 1.34-1.44 (m, 2H) 1.80-1.95 (m, 2H)3.14-3.21 (m, 2H) 3.67 (br s, 3H) 3.97 (br s, 1H) 6.40 (br s, 1H) 7.45(d, 7.0 Hz, 1H) 7.54 (m, 1H) 7.84 (d, J=7.4 Hz, 1H) 8.13 (d, J=5.1 Hz,1H).

The compounds listed below were prepared using procedures analogous tothe preparation of Example 4A using the appropriate starting materialsand isolated as either their free base or salt form (generally, thetrifluoroacetate or hydrogen chloride salt).

(S)-Methyl1-(4-(2-tert-butyl-4-(2-fluoro-3-(propylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(4B)

¹H NMR (400 MHz, CD₃OD) δ1.02 (t, J=7.4 Hz, 6H) 1.56 (s, 9H) 1.77-1.92(m, 2H) 2.98 (br s, 1H) 3.09-3.16 (m, 2H) 3.25 (br s, 1H) 3.61 (s, 3H)3.79 (br s, 1H) 6.97 (br s, 1H) 7.30-7.47 (m, 2H) 7.65-7.77 (m, 1H) 8.18(d, J=3.9 Hz, 1H). LCMS (m/z) (M+H)=548.2, Retention time (t_(R))=0.65minute.

(S)-Methyl1-(4-(2-cyclopropyl-4-(2-fluoro-3-(propylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(4C)

¹H NMR (400 MHz, CD₃OD) δ 1.05 (t, J=7.4 Hz, 3H) 1.09-1.19 (m, 3H) 1.38(t, J=4.3 Hz, 2H) 1.43-1.54 (m, 2H) 1.80-1.93 (m, 2H) 2.58 (br s, 1H)3.15-3.23 (m, 2H) 3.53-3.63 (m, 1H) 3.65 (s, 4H) 3.95 (d, J=7.0 Hz, 1H)6.74-6.86 (m, 1H) 7.38-7.51 (m, 2H) 7.78 (m, 1H) 8.27 (d, J=6.3 Hz, 1H).LCMS (m/z) (M+H)=532.2, Retention time (t_(R))=0.62 minute.

(S)-Methyl1-(4-(2-cyclopropyl-4-(3-methyl-5-(1-methylethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(4D)

¹H NMR (400 MHz, CD₃OD) δ 1.06 (d, J=6.3 Hz, 3H) 1.24 (m, 10H) 2.31 (s,3H) 2.38-2.55 (m, 1H) 2.76-3.07 (m, 1H) 3.43-3.74 (m, 5H) 3.78-4.03 (m,1H) 6.37-6.65 (m, 1H) 7.07 (s, 1H) 7.14 (br s, 1H) 7.21 (br s, 1H)7.92-8.24 (m, 1H). LCMS (m/z) (M+H)=528.2, Retention time (t_(R))=0.62minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(2-fluoro-3-(3,3,3-trifluoropropylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(4E)

¹H NMR (400 MHz, CD₃OD) δ 1.04 (br. s., 3H) 1.56 (s, 9H) 2.62-2.86 (m,2H) 2.91-3.05 (m, 1H) 3.36-3.46 (m, 3H) 3.61 (s, 3H) 3.78 (br s, 1H)6.96-7.10 (m, 1H) 7.40 (m, 1H) 7.47 (m, 1H) 7.71 (m, 1H) 8.18 (d, J=3.5Hz, 1H). LCMS (m/z) (M+H)=602.2, Retention time (t_(R))=0.68 minute.

(S)-Methyl1-(4-(2-tert-butyl-5-(5-chloro-2-fluoro-3-(propylsulfonamido)phenyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(4F)

LCMS (m/z) (M+H)=582.4, Retention time (t_(R))=0.73 minute.

N-(3-(5-(2-(2-Cyanoethylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide(4G)

¹H NMR (400 MHz, CD₃OD) δ 1.03 (t, J=7.4 Hz, 3H) 1.22-1.31 (m, 2H)1.32-1.43 (m, 2H) 1.78-1.92 (m, 2H) 2.30-2.42 (m, 1H) 2.53 (br s, 2H)3.10-3.19 (m, 2H) 3.48 (m, 2H) 7.33-7.44 (m, 2H) 7.72 (m, 1H) 8.27 (d,J=5.5 Hz, 2H). LCMS (m/z) (M+H)=470.1, Retention time (t_(R))=0.57minute.

3-(4-(2-Cyclopropyl-4-(2-fluoro-3-(propylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanamide(4H)

LCMS (m/z) (M+H)=488.1, Retention time (t_(R))=0.48 minute.

(S)-Methyl1-(4-(2-tert-butyl-4-(2,4-difluoro-3-(propylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(4I)

LCMS (m/z) (M+H)=566.2, Retention time (t_(R))=0.68 minute.

(S)-Methyl1-(4-(2-cyclopropyl-4-(3-(propylsulfonamido)phenyl)-1H-imidazol-5-pyrimidin-2-ylamino)propan-2-ylcarbamate(4J)

¹H NMR (300 MHz, CD₃CO₂D) δ 1.00 (t, J=7.5 Hz, 3H), 1.22 (d, J=6.7 Hz,3H), 1.28-1.43 (m, 2H), 1.51 (m, 2H), 1.72-1.89 (m, 2H), 2.62 (m, 1H),3.18 (m, 2H), 3.64-3.80 (m, 1H), 3.73 (s, 3H), 3.82-3.94 (m, 1H), 4.11(m, 1H), 6.77 (d, J=6.2 Hz, 1H), 7.33-7.63 (m, 4H), 8.20 (d, J=6.2 Hz,1H). LCMS (m/z) (M+H)=514.4, Retention time (t_(R))=0.57 minute.

(S)-Methyl1-(4-(2-cyclopropyl-4-(3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(4K)

¹H NMR (300 MHz, CD₃CO₂D) δ 1.22 (d, J=6.7 Hz, 3H), 1.37 (m, 2H), 1.50(m, 2H), 2.62 (m, 1H), 3.07 (s, 3H), 3.18 (m, 1H), 3.72 (s, 3H), 3.88(m, 1H), 4.10 (m, 1H), 6.79 (d, J=6.2 Hz, 1H), 7.36-7.69 (m, 4H), 8.21(d, J=6.2 Hz, 1H). LCMS (m/z) (M+H)=486.2, Retention time (t_(R))=0.50minute.

Example 5 Preparation of (S)-methyl1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(5A)

A glass bomb was charged with (S)-methyl1-(4-(5-bromo-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(I-1b, 9.0 g, 22.7 mmol), solid anhydrous Na₂CO₃ (9.65 g, 91 mmol),2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(SM-8, 16.65 g, 65% by ¹H NMR assay, 39.8 mmol), DME (60 ml) and water(30 mL). The resulting mixture was thoroughly sparged with Argon for 10minutes, followed by addition of Pd(PPh₃)₄ (2.63 g, 2.28 mmol), andanother Argon sparge was repeated for 5 minutes. The reaction vessel wassealed, heated at 105° C. in an oil bath for 17 hours. LCMS indicatedcomplete conversion, and the reaction was allowed to cool to roomtemperature. The reaction mixture was partitioned between EtOAc (60 mLand water (50 ml) and the layers separated. The organic portion waswashed with brine (60 mL), dried (Na₂SO₄), concentrated to a light brownoil. Purification by flash chromatography (SiO₂, 0-5% MeOH in DCM)furnished (S)-methyl1-(4-(5-(3-amino-2-chloro-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(9.71 g, 21.1 mmol, 93%) as a light yellow solid: LCMS (m/z) 460.1(MH⁺), t_(R)=0.55 minute, ¹H NMR (400 MHz, CD₃CO₂D) δ 1.20 (d, J=6.7 Hz,3H), 1.26 (app br s, 2H), 1.31-1.48 (m, 2H), 2.45-2.58 (m, 1H),3.11-3.27 (m, 1H), 3.71 (s, 3H), 3.74-3.85 (m, 1H), 4.00-4.17 (m, 1H),6.51 (d, J=6.3 Hz, 1H), 6.58-6.71 (m, 1H), 6.71-6.83 (m, 1H), 8.15 (d,J=6.7 Hz, 1H).

To a solution of (S)-methyl1-(4-(5-(3-amino-2-chloro-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(8.36 g, 18.2 mmol) in dry pyridine (40 mL) at 0° C. was addedmethanesulfonyl chloride (5.6 mL, 72.7 mmol), followed by the removal ofcold bath. The reaction was stirred at room temperature for 2 hours.LCMS indicated complete conversion to sulfonylated products and thereaction was quenched with water (2.5 mL) at 0° C. The resulting mixturewas stirred at 0° C. for an additional 15 minutes and then heated in a50° C. oil bath for 20 minutes. After allowing to cool to roomtemperature, the volatile components were removed by rotary evaporatorin vacuo, and then dried under high vacuum. The resulting residue wasdiluted with DME (100 mL), followed by the addition of saturated aqueousNa₂CO₃ solution (75 mL). The reaction mixture was heated at 55° C. for 1hour. LCMS indicated complete conversion to the desired product. Thereaction was allowed to cool to room temperature and partitioned uponstanding. The layers were separated and the organic portion was filteredthrough a sintered funnel and filter cake was thoroughly rinsed withmethanol. The combined filtrates were again filtered through a sinteredfunnel and the filtrates concentrated. The resulting residue wasdissolved in aqueous NaOH (0.20 M, 150 ml) and the solution was washedwith EtOAc (75, 50 mL). The combined organic portions were backextracted with aqueous 0.2 N NaOH solution (50, 25 mL). The combinebasic aqueous phases were acidified with aqueous 3.0 M HCl solution (15mL) to pH 5-6, and milky product suspension was extracted into EtOAc(150 mL). The organic portion was washed with 0.1M sodium phosphatebuffer (pH 7, 50 ml), dried (Na₂SO₄), and concentrated to a light yellowfoam (9.2 g) which was dissolved in DCM (120 mL) and treated with apalladium scavenger (5.0 g, SiliaBond DMT, loading 0.57 mmol/g,Silicycle, Catalog Number R79030B) overnight. Further dilution with DCM(120 mL) and methanol (12 mL) at 30° C. followed by filtration throughCelite and concentration furnished a light yellow residue (8.2 g).Crystallization from ethanol (90 mL) followed by drying under highvacuum in a drying pistol (P₂O₅, 100° C.) provided (5)-methyl1-(4-(5-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(5A, 7.5 g, 13.9 mmol, 76%) was obtained as a fine white powder: LCMS(m/z) 538.1 (MH⁺), t_(R)=0.56 minute; ¹H NMR (300 MHz, CD₃CO₂D) δ 1.20(d, J=6.7 Hz, 5H), 1.25-1.41 (m, 2H), 2.35-2.56 (m, 1H), 3.13 (s, 3H),3.16-3.27 (m, 1H), 3.71 (s, 3H), 3.77 (dd, J=13.04, 3.37 Hz, 1H),3.97-4.21 (m, 1H), 6.42 (d, J=6.45 Hz, 1H), 7.22 (dd, J=8.20, 2.93 Hz,1H), 7.62 (dd, J=9.67 Hz, 2.93 Hz, 1H), 8.10-8.30 (m, 1H).

Alternatively, (S)-methyl1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(5A) can also be prepared using the following procedure.

A 1-Liter, 3-necked round bottom flask was equipped with a mechanicalstirrer, a thermometer a reflux condenser, a heating mantle and anitrogen inlet/outlet, was charged with 450 mL of toluene. The solventwas heated at reflux for 2 hours. The solvent was cooled to roomtemperature under nitrogen and was used for the reaction. Another1-Liter, three-necked, round-bottomed flask, equipped with a mechanicalstirrer, a thermometer, a reflux condenser, a heating mantle and anitrogen inlet/outlet, was charged at with sodium tert-butoxide (25 g),1,3-dibromo-2-chloro-5-fluorobenzene (50 g), 400 mL of degassed toluene,and benzophenone imine (33 g). The mixture was stirred at 22-25° C. for10 minutes. A vacuum/nitrogen-fill cycle was performed three times. Tothe mixture was added racemic BINAP (3.8 g) and Pd₂ dba₃ (1.9 g) at22-25° C. The mixture was heated to an internal temperature of 83-87° C.over 1 hour. (Upon reaching the batch temperature at 80° C., the outletvent was closed off). The mixture was heated at 83-87° C. for 3 hours.The mixture was cooled to 22-25° C. and 400 mL of water was added. Themixture was stirred for 30 minutes. The organic layer was separated. Theaqueous layer was extracted with 100 mL of toluene. The combined organicphase was washed with 200 mL of water.

To the above solution (˜600 mL) was transferred to a 2-Liter,three-necked, round-bottomed flask, equipped with a mechanical stirrer,a thermometer, a reflux condenser, a heating mantle and a nitrogeninlet/outlet. To the solution was added 200 mL of 6 N aqueoushydrochloric acid. The mixture was stirred and heated at 57-63° C. for 4hours. The mixture was cooled to 22-25° C. The mixture was distilledunder vacuum to a final volume of <500 mL. To the biphasic solution wasadded 1,000 mL of heptane. The resulting slurry was cooled to 0-5° C.and stirred for 2 hours. The dark bilayer slurry was filtered through apolypropylene filter paper with suction. The filter cake was washed with2×50 mL of heptane. The solids were dried in an oven at 50° C. for 5hours under vacuum to afford 33.8 g of crude hydrogen chloride salt of3-bromo-2-chloro-5-fluoroaniline.

The above solids were transferred to a 1-L, three-necked, round-bottomedflask, containing 200 mL of toluene and 100 g of 20% (w/w) sodiumcarbonate solution. The mixture was stirred at 22-25° C. for 30 minutesor until all solids have dissolved. The organic phase was separated andwashed with Separate layers. Wash the organic layer with 50 g of 20%(w/w) of sodium chloride solution. The solution was distilled undervacuum to a final volume of ˜75 mL and then held it at 22-25° C. Thesolution was then diluted with 90 mL of heptane and filtered through abed of 100 g of silica gel (60-230 mesh). The product off the silica gelpad bed was washed with 1.1 L of a solution of toluene/heptane v/v, 1/3)by applying a slight vacuum pressure. The filtered solution wasdistilled to a final volume of ˜70 mL and diluted with 250 mL ofheptane. While maintaining the internal temperature below 27° C., 6 Naqueous hydrochloric acid (60 mL) as added drop wise over 15 minutes.The resulting white slurry was stirred at 20-25° C. for 5 hours. Thebatch was then cooled to 0-5° C. over 30 minutes and stirred at thistemperature for 3 hours. The slurry was filtered through a polypropylenefilter paper with suction and the filtered solid was washed with 80 mLof heptane. The solids were dried under vacuum in an oven at 50° C. toconstant weight (18 hours) to obtain 26 g (57%) of3-bromo-2-chloro-5-fluoroaniline as the hydrogen chloride salt (whitesolid with HPLC purity>98%).

A mixture of 3-bromo-2-chloro-5-fluoroaniline hydrogen chloride (5.0 g,19.163 mmol), PiN₂B₂ (6.81 g, 26.818 mmol), P(C₆H₁₁)₃ (0.536 g, 1.912mmol), potassium acetate (5.632 g, 57.411 mmol) and 110 mL toluene in a250 mL, 3-necked round bottomed flask was heated to reflux. About 10 mLof solvent was distilled at atmospheric pressure. The mixture was cooledto approximately 60° C. followed by the addition of Pd₂(dba)₃ (0.877 g.0.958 mmol). The reaction mixture was heated at 110° C. for 0.5 hours.HPLC of the reaction mixture indicated completion of the reaction.Heating was stopped and reaction mixture was cooled to 20-22° C. Themixture was filtered through pad of Celite and basic alumina. The blackcake was washed with 100 mL of toluene. The filtrate was evaporatedunder vacuum. The residue was used as such for the next reaction.

In a 1 Liter round bottom, 4-neck flask equipped with an overheadstirrer, thermocouple, condenser, heating mantle and nitrogeninlet/outlet were placed of4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine(50 g, 0.116 mol), (S)-methyl 1-aminopropan-2-ylcarbamate hydrogenchloride salt (25.5 g, 0.1512 mol), Na₂CO₃ (49.3 g. 0.4653 mol) and 400mL of DMSO. The mixture was stirred and heated at 90° C. After 16 hours,the reaction was complete as indicated by disappearance of4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazol-5-yl)-2-chloropyrimidineby HPLC. The reaction mixture was cooled to 25° C. and then added slowlyto a mixture of water (1.5 L) and MTBE (500 mL). The mixture was stirreduntil all solids had dissolved (45 minutes). The organic phase wasseparated and the aqueous phase was extracted once with MTBE (500 mL).The combined organic phase was washed once with 10% citric acid solution(250 mL) and once with water (250 mL) and then with brine (150 mL). Theorganic phase was dried over anhydrous MgSO₄, filtered and concentratedunder reduced pressure on the rotary evaporator to an oil (66 g). Theproduct ((S)-methyl1-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate)contained some residual solvent and was used as such in the next step.

A 100-mL, 3-necked round bottomed flask with a small magnetic stirrerwas charged with (S)-methyl1-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(5.746 g, 10.934 mmol),3-bromo-2-chloro-N-(diphenylmethylene)-5-fluoroaniline (4.15 g, 15.322mmol), Na₂CO₃ (3.48 g, 32.83 mmol), degassed DME (57 mL) and degassedwater (5.7 mL). Nitrogen gas was bubbled through the mixture for 2-3minutes followed by the addition of Pd(PPh₃)₄ (1.265 g, 1.095 mmol). Themixture was heated at 82° C. HPLC of the reaction mixture after 22 hoursindicated completion.

The reaction mixture was evaporated under vacuum. The residue wasstirred with ethyl acetate (100 mL) and water (50 mL). The mixture wasfiltered and the organic layer was separated and saved. The aqueouslayer was extracted once with ethyl acetate (50 mL). The combinedorganic phase was washed once with water (50 mL), dried over MgSO₄,filtered and evaporated under vacuum to give 15.349 (26.01 mmol,237.61%) of crude (S)-methyl1-(4-(4-(3-amino-2-chloro-5-fluorophenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(contains PPh₃O, catalyst, solvent and other impurities) as a dark brownoil. The crude product was used as such for the next hydrolysis step.

A mixture of the crude (S)-methyl1-(4-(4-(3-amino-2-chloro-5-fluorophenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(15.349 g), p-toluenesulfonic acid (3.64 g, 21.132 mmol) and methanol(70 mL) in a 100 mL, 3-necked round bottomed flask was heated at refluxfor 1 hour. HPLC indicted completion of reaction. The reaction mixturewas evaporated under vacuum and the residue was stirred with 2 N HCl (50mL) and ethyl acetate (75 mL). The aqueous layer was separated and theorganic layer was extracted once with 2 N HCl (40 mL). The combinedaqueous layers were extracted once with ethyl acetate (50 mL) and thenneutralized with aq NaOH (4 N). The product was extracted with 2×50 mLof ethyl acetate. The organic layer was washed once with water (40 mL),dried over MgSO₄ and evaporated under vacuum to give 5.136 g (11.190mmol) of crude (S)-methyl1-(4-(4-(3-amino-2-chloro-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamateas a brown oil.

A 3-necked 100 mL round bottomed flask was charged with crude (S)-methyl1-(4-(4-(3-amino-2-chloro-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(5.136 g), THF (50 mL) and triethylamine (6.21 mL, 44.63 mmol). Thesolution was cooled to 0-5° C. and MeSO₂Cl (3.836 g, 33.508 mmol) wasadded slowly (highly exothermic) keeping the batch temperature<5° C.HPLC of the reaction mixture after 3 hours indicated completion of thereaction. 50% aqueous NaOH (20 mL) was slowly added to the reactionmixture at 0-5C. The addition was exothermic. The batch temperature rosefrom approximately 2° C. to 19° C. within a few minutes. The mixture wasstirred at 19° C. HPLC of the reaction mixture after 16 hours indicatedcompletion of the reaction. The reaction mixture was evaporated undervacuum at 22-25° C. to remove THF. The mixture was diluted with waterand the mixture was extracted with 2×75 mL of TBME. To the aqueous phasewas added ethyl acetate (100 mL). The pH of the aqueous phase was thenadjusted to 5.75-6.0 by slow addition of a 3 N HCl solution. The organiclayer was separated and the aqueous phase extracted with ethyl acetate(2×50 mL). The ethyl acetate phases were combined and washed with water(2×50 mL), dried over MgSO₄, and evaporated under vacuum to give a lightyellow foamy solid (3.42 g, 6.357 mmol). To the crude product (3.42 g)was added isopropanol (35 mL) and the mixture was heated at reflux for10 minutes. The suspension was cooled to 20-22° C. and then to 0-5° C.The mixture was stirred at 0-5° C. for 30 minutes and then filtered. Thecake was washed with ice-cold isopropanol. The product was dried at 65°C. in vacuo for 18 hours to give 2.516 g (4.676 mmol, HPLC purity>98%)of the desired product (S)-methyl1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate(5A).

PHARMACOLOGICAL DATA

Utility for the compounds of the present invention is supported by thedata observed in one or more of the following assays.

Raf/Mek Amplified Luminescence Proximity Homogeneous Assay

(Alpha Screen)

Buffers

Assay buffer: 50 mM Tris, pH 7.5, 15 mM MgCl₂, 0.01% Bovine SerumAlbumin (BSA), 1 mM dithiothreitol (DTT)

Stop buffer: 60 mM ethylenediaminetetraacetic acid (EDTA), 0.01% Tween®20

Bead buffer: 50 mM Tris, pH 7.5, 0.01% Tween® 20

Materials

b-Raf(V600E), active

biotinylated Mek, kinase dead

Alpha Screen detection kit (available from PerkinElmer™, #6760617R)

Anti phospho-MEK1/2 (available from Cell Signaling Technology, Inc.#9121)

384 well assay plates (White Greiner® plates, #781207)

Assay Conditions

b-Raf(V600E) approximately 4 pM

c-Raf approximately 4 nM

biotinylated Mek, Kinase dead approximately 10 nM

ATP 10 μM

Pre-incubation time with compounds 60 minutes at room temperature

Reaction time 1 or 3 hours at room temperature

Assay Protocol

Raf and biotinylated Mek, kinase dead, were combined at 2× finalconcentrations in assay buffer (50 mM Tris, pH 7.5, 15 mM MgCl₂, 0.01%BSA and 1 mM DTT) and dispensed 10 μl per well in assay plates (Greinerwhite 384 well assay plates #781207) containing 0.5 μl of 40× of a rafkinase inhibitor test compound diluted in 100% DMSO. The plate wasincubated for 60 minutes at room temperature.

The Raf kinase activity reaction was started by the addition of 10 μLper well of 2×ATP diluted in assay buffer. After 3 hours (bRaf(V600E))or 1 hour (c-Raf), the reactions were stopped with the addition of 10 μLof stop reagent (60 mM EDTA). Phosphorylated product was measured usinga rabbit anti-p-MEK (Cell Signaling, #9121) antibody and the AlphaScreen IgG (ProteinA) detection Kit (PerkinElmer #6760617R), by theaddition of 30 μL to the well of a mixture of the antibody (1:2000dilution) and detection beads (1:2000 dilution of both beads) in beadbuffer (50 mM Tris, pH 7.5, 0.01% Tween20). The additions were carriedout under dark conditions to protect the detection beads from light. Alid was placed on top of the plate and incubated for 1 hour at roomtemperature, then the luminescence was read on a PerkinElmer Envisioninstrument. The concentration of each compound for 50% inhibition (IC₅₀)was calculated by non-linear regression using XL Fit data analysissoftware.

Mutant b-Raf(V600E) IC₅₀ data for representative compounds of theinvention in the Raf/Mek Amplified Luminescence Proximity HomogeneousAssay are shown in the Table I below. Each of the compounds were testedas either their free base or salt form indicated in the table below.

TABLE 1 Ex. mut-B-RAF No. Compound Name IC50 (μM) 1A (S)-methyl1-(4-(4-(5-chloro-2-fluoro-3- 0.00020(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate 1B (S)-Methyl1-(4-(2-cyclopropyl-4-(2-fluoro-5- 0.0002methyl-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate 1C (S)-Methyl1-(4-(2-tert-butyl-4-(3-chloro-5- 0.00032(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1D(S)-Methyl 1-(4-(2-tert-butyl-4-(3-chloro-5- 0.23500(trifluoroethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1E(S)-Methyl 1-(4-(2-tert-butyl-4-(3-chloro-5- 0.0001(propylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1F(S)-Methyl 1-(4-(2-tert-butyl-4-(3-chloro-5- 0.0001(cyclopropanesulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1G(S)-Methyl 1-(4-(2-tert-butyl-4-(3-chloro-5-(2- 0.0003methylpropylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1HMethyl (2S)-1-(4-(2-tert-butyl-4-(3-chloro-5-(1- 0.0005methylpropylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1I(S)-Methyl 1-(4-(2-tert-butyl-4-(3-chloro-5- 0.0001(ethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1J(S)-Methyl 1-(4-(2-tert-butyl-4-(3-chloro-5-(1- 0.00135methylethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1K(S)-Methyl 1-(4-(2-tert-butyl-4-(3-methoxy-4- 0.18900methyl-5-(1-methylethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate,trifluoroacetate salt 1L (S)-Methyl 1-(4-(2-tert-butyl-4-(3- 0.15700(cyclopropanesulfonamido)-5-methoxy-4-methylphenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1M (S)-Methyl1-(4-(4-(3-chloro-5-(1- 0.00063methylethylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate,trifluoroacetate salt 1N (S)-Methyl 1-(4-(2-tert-butyl-4-(5-chloro-3-0.20400 (cyclopropanesulfonamido)-2-methylphenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate,trifluoroacetate salt 1O (S)-Methyl1-(4-(2-tert-butyl-4-(5-chloro-2-methyl- 0.067203-(1-methylethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate 1P (S)-Methyl1-(4-(2-tert-butyl-5-(3- 0.01120 (difluoromethoxy)-5-(1-methylethylsulfonamido)phenyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1Q(S)-Methyl 1-(4-(2-tert-butyl-4-(3-methyl-5-(1- 0.00312methylethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1R(S)-Methyl 1-(4-(2-tert-butyl-4-(3- 0.03450(methylsulfonamido)phenyl)-1H-imidazol-5 -yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1S(S)-Methyl 1-(4-(4-(3-chloro-5- 0.00048(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate,trifluoroacetate salt 1T (S)-Methyl 1-(4-(4-(2-chloro-3- 0.00047(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate, hydrogenchloride salt 1U (S)-Methyl 1-(4-(2-cyclopropyl-4-(2-fluoro-3- 0.00055(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1VMethyl (2S)-1-(4-(2-cyclopropyl-4-(2,5-difluoro-3- 0.0002(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate 1W (S)-Methyl1-(4-(5-(5-chloro-2-fluoro-3- 0.00089(propylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate,trifluoroacetate salt 1X (S)-Methyl1-(4-(2-cyclopropyl-4-(2,5-dichloro-3- 0.00018(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, hydrogen chloride salt 1Y(S)-Methyl 1-(4-(5-(5-chloro-3- 0.00018(cyclopropanesulfonamido)-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2- ylamino)propan-2-ylcarbamate,hydrogen chloride salt 1Z (S)-Methyl1-(4-(5-(5-chloro-3-(ethylsulfonamido)- 0.000242-fluorophenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, hydrogen chloride salt 1AA(S)-Methyl 1-(4-(5-(5-chloro-2-fluoro-3-(3,3,3- 0.0006trifluoropropylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate, hydrogenchloride salt 1AB (S)-Methyl 1-(4-(4-(2-chloro-5-methyl-3- 0.0011(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate 1AC (S)-Methyl1-(4-(5-(5-chloro-3- 0.00026(cyclopropylmethylsulfonamido)-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2- ylamino)propan-2-ylcarbamate,trifluoroacetate salt 1AD (S)-Methyl1-(4-(4-(2-chloro-3-(ethylsulfonamido)- 0.000435-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate 1AE (S)-Methyl1-(4-(4-(2-chloro-3- 0.00030(cyclopropanesulfonamido)-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2- ylamino)propan-2-ylcarbamate1AF Methyl (2S)-1-(4-(4-(2-chloro-6-fluoro-3- 0.00045(propylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate,trifluoroacetate salt 1AG (S)-Methyl1-(4-(2-tert-butyl-4-(2-chloro-5-fluoro- 0.00103-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1AH(S)-Methyl 1-(4-(2-tert-butyl-4-(2-chloro-5-fluoro- 0.00103-(propylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1AI(S)-Methyl 1-(4-(2-tert-butyl-4-(5-chloro-2-fluoro- 0.000283-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1AJ(S)-Methyl 1-(4-(2-tert-butyl-4-(5-chloro-3- 0.00046(ethylsulfonamido)-2-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1AKN-(2-Chloro-3-(5-(2-(2- 0.011cyanopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)phenyl)methanesulfonamide 1AL (S)-Methyl1-(4-(5-(5-chloro-2-fluoro-3- 0.0010 (methylsulfonamido)phenyl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, hydrogen chloride salt 1AM (S)-Methyl1-(4-(5-(2-fluoro-5-methyl-3- 0.0010 (methylsulfonamido)phenyl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate 1AN N-(2-Chloro-3-(2-cyclopropyl-5-(2-0.00039 (propylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)propane-1-sulfonamide, trifluoroacetate salt 1AO (S)-Methyl1-(4-(5-(2-chloro-3- 0.0010 (methylsulfonamido)phenyl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 1APN-(2-Chloro-3-(2-cyclopropyl-5-(2- 0.0050(propylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide, trifluoroacetate salt 1AQN-(2-Chloro-3-(2-cyclopropyl-5-(2- 0.011(ethylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide, trifluoroacetate salt 1ARN-(2-Chloro-3-(2-cyclopropyl-5-(2- 0.0050(isobutylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide, trifluoroacetate salt 1ASN-(2-Chloro-3-(2-cyclopropyl-5-(2- 0.0010(ethylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)propane-1-sulfonamide, trifluoroacetate salt 1ATN-(2-Chloro-3-(2-cyclopropyl-5-(2- 0.025(isopropylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide, trifluoroacetate salt 1AUN-(2-Chloro-3-(2-cyclopropyl-5-(2- 0.0050(isopropylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)propane-1-sulfonamide, trifluoroacetate salt 1AV(R)-Methyl 1-(4-(4-(2-chloro-5-fluoro-3- 0.011(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate 1AW (S)-Methyl1-(4-(5-(5-chloro-2-fluoro-3-(4- 0.0010fluorophenylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate,trifluoroacetate salt 1AX (S)-Methyl 1-(4-(5-(5-chloro-2-fluoro-3-(3-0.00033 fluorophenylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate,trifluoroacetate salt 1AYN-(2-Chloro-3-(5-(2-(2-cyanoethylamino)pyrimidin- 0.000234-yl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide 1AZN-(2-Chloro-3-(5-(2-(2-cyanoethylamino)pyrimidin- 0.000294-yl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)-5-methylphenyl)methanesulfonamide 1BAN-(3-(5-(2-(2-Cyanoethylamino)pyrimidin-4-yl)-2- 0.00037(1-methylcyclopropyl)-1H-imidazol-4-yl)-2-fluoro-5-methylphenyl)methanesulfonamide 1BBN-(5-Chloro-3-(5-(2-(2-cyanoethylamino)pyrimidin- 0.000114-yl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)-2-fluorophenyl)methanesulfonamide 1BCN-(2-Chloro-3-(5-(2-(2-cyanoethylamino)pyrimidin- 0.00104-yl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)phenyl)methanesulfonamide 1BDN-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butyl-1H- 0.0030imidazol-4-yl)-5-chloro-2- fluorophenyl)methanesulfonamide,trifluoroacetate salt 1BEN-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butyl-1H- 0.00013imidazol-4-yl)-5-chloro-2-fluorophenyl)-2,6- difluorobenzenesulfonamide,trifluoroacetate salt 1BF N-(3-(5-(2-Aminopyrimidin-4-yl)-2-cyclopropyl-0.00010 1H-imidazol-4-yl)-5-chloro-2-fluorophenyl)-2,6-difluorobenzenesulfonamide, trifluoroacetate salt 1BGN-(3-(5-(2-Aminopyrimidin-4-yl)-2-cyclopropyl- 0.00401H-imidazol-4-yl)-5-chloro-2- fluorophenyl)methanesulfonamide,trifluoroacetate salt 1BHN-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butyl-1H- 0.00008imidazol-4-yl)-5-chloro-2-fluorophenyl)propane-1- sulfonamide,trifluoroacetate salt 1BI (S)-Methyl 1-(4-(4-(2-chloro-3-(2,6- 0.00010difluorophenylsulfonamido)-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2- ylamino)propan-2-ylcarbamate,trifluoroacetate salt 1BJN-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butyl-1H- 0.0050imidazol-4-yl)-2-chloro-5- fluorophenyl)methanesulfonamide,trifluoroacetate salt 1BKN-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butyl-1H- 0.00022imidazol-4-yl)-2-chlorophenyl)-2,6- difluorobenzenesulfonamide,trifluoroacetate salt 1BLN-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butyl-1H- 0.055imidazol-4-yl)-2-chlorophenyl)methanesulfonamide, trifluoroacetate salt1BM (S)-Methyl 1-(4-(4-(5-chloro-3-(3,5- 0.00037difluorophenylsulfonamido)-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2- ylamino)propan-2-ylcarbamate,trifluoroacetate salt 1BN (S)-Methyl 1-(4-(4-(5-chloro-2-fluoro-3-(4-0.0070 (trifluoromethyl)phenylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2- ylamino)propan-2-ylcarbamate,trifluoroacetate salt 1BO (S)-Methyl 1-(4-(2-cyclopropyl-4-(2-fluoro-5-0.00025 methyl-3-(2,2,2-trifluoroethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate 1BPN-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butyl-1H- 0.00026imidazol-4-yl)-2-chloro-5-fluorophenyl)-2,6- difluorobenzenesulfonamide,trifluoroacetate salt 1BQ N-(3-(5-(2-Aminopyrimidin-4-yl)-2-cyclopropyl-0.012 1H-imidazol-4-yl)-2-chloro-5- fluorophenyl)methanesulfonamide,trifluoroacetate salt 1BR N-(3-(5-(2-Aminopyrimidin-4-yl)-2-cyclopropyl-0.00019 1H-imidazol-4-yl)-2-chloro-5-fluorophenyl)-2,6-difluorobenzenesulfonamide, trifluoroacetate salt 1BSN-(3-(5-(2-Aminopyrimidin-4-yl)-2-cyclopropyl- 0.000201H-imidazol-4-yl)-2-chloro-5- fluorophenyl)propane-1-sulfonamide,trifluoroacetate salt 1BT (S)-Methyl 1-(4-(4-(5-chloro-2-fluoro-3-0.00023 (methylsulfonamido)phenyl)-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate,trifluoroacetate salt 1BU (S)-Methyl 1-(4-(4-(2-chloro-5-fluoro-3-0.0010 (methylsulfonamido)phenyl)-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate,trifluoroacetate salt 1BV N-(2-Chloro-3-(2-cyclopropyl-5-(2- 0.0010(methylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)-2,6-difluorobenzenesulfonamide, trifluoroacetate salt 1BWN-(2-Chloro-3-(2-cyclopropyl-5-(2- 0.031(methylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)methanesulfonamide, trifluoroacetate salt 1BXN-(2-Chloro-3-(2-cyclopropyl-5-(2- 0.00011(methylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-5-fluorophenyl)propane-1-sulfonamide 1BY (S)-Methyl1-(4-(4-(2-chloro-5-fluoro-3- 2.04(methylsulfonamido)phenyl)-2-(2,4-difluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate 1BZ(S)-Methyl 1-(4-(4-(2-chloro-5-fluoro-3- 0.002(methylsulfonamido)phenyl)-2-(4-(trifluoromethyl)-phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)- propan-2-ylcarbamate 2AN-(5-Chloro-3-(5-(2-(2-cyanoethylamino)pyrimidin- 0.000084-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2- fluorophenyl)methanesulfonamide2B (S)-Methyl 1-(4-(2-tert-butyl-4-(3- 0.00027(cyclopropanesulfonamido)-2-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate,trifluoroacetate salt 2C (S)-Methyl 1-(4-(2-tert-butyl-4-(2-fluoro-3-.00061 (methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 2D(S)-Methyl 1-(4-(2-tert-butyl-4-(2-fluoro-3-(1- .00078methylethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 2EN-(3-(5-(2-(2-Cyanoethylamino)pyrimidin-4-yl)-2- 0.004cyclopropyl-1H-imidazol-4-yl)-2- fluorophenyl)methanesulfonamide 2FMethyl (2S)-1-(4-(4-(2-chloro-6-fluoro-3- 0.005(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamate,trifluoroacetate salt 2G N-(2-Chloro-3-(5-(2-((1-cyanocyclopropyl)-0.035 methylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)phenyl)methanesulfonamide 2HN-(3-(5-(2-Aminopyrimidin-4-yl)-2-cyclopropyl- 0.00101H-imidazol-4-yl)-2-chlorophenyl)-2,6- difluorobenzenesulfonamide 2IN-(2-Chloro-3-(2-cyclopropyl-5-(pyrimidin-4-yl)- 0.00101H-imidazol-4-yl)-5-fluorophenyl)-2,6- difluorobenzenesulfonamide,trifluoroacetate salt 2JN-(2-Chloro-3-(2-cyclopropyl-5-(pyrimidin-4-yl)- 0.0871H-imidazol-4-yl)-5- fluorophenyl)methanesulfonamide, trifluoroacetatesalt 2K N-(2-Chloro-3-(2-cyclopropyl-5-(pyrimidin-4-yl)- 0.00401H-imidazol-4-yl)-5-fluorophenyl)propane-1- sulfonamide,trifluoroacetate salt 3A-2N-(3-(2-Cyclopropyl-5-(2-(methylamino)pyrimidin- 0.5784-yl)-1H-imidazol-4-yl)-2-fluorophenyl)- methanesulfonamide, hydrogenchloride salt 3B (S)-N-(3-(2-Cyclopropyl-5-(2-(2-hydroxy- 0.028propylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-2-fluorophenyl)methanesulfonamide, hydrogen chloride salt 4A-3 Methyl(2S)-1-(4-(2-cyclopropyl-4-(2,5-difluoro-3- 0.00013(methylsulfonamido)-phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate 4B (S)-Methyl1-(4-(2-tert-butyl-4-(2-fluoro-3- .00038(propylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 4C(S)-Methyl 1-(4-(2-cyclopropyl-4-(2-fluoro-3- 0.00016(propylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 4D(S)-Methyl 1-(4-(2-cyclopropyl-4-(3-methyl-5-(1- 0.00096methylethylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 4E(S)-Methyl 1-(4-(2-tert-butyl-4-(2-fluoro-3-(3,3,3- 0.00108trifluoropropylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 4F(S)-Methyl 1-(4-(2-tert-butyl-5-(5-chloro-2-fluoro- 0.000533-(propylsulfonamido)phenyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 4GN-(3-(5-(2-(2-Cyanoethylamino)pyrimidin-4-yl)-2- 0.00013cyclopropyl-1H-imidazol-4-yl)-2- fluorophenyl)propane-1-sulfonamide,trifluoroacetate salt 4H 3-(4-(2-Cyclopropyl-4-(2-fluoro-3- 0.002(propylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanamide, trifluoroacetate salt 4I (S)-Methyl1-(4-(2-tert-butyl-4-(2,4-difluoro-3- 0.00012(propylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 4J(S)-Methyl 1-(4-(2-cyclopropyl-4-(3- 0.0010(propylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 4K(S)-Methyl 1-(4-(2-cyclopropyl-4-(3- 0.0080(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate, trifluoroacetate salt 5A(S)-Methyl 1-(4-(4-(2-chloro-5-fluoro-3- 0.0004(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2- ylcarbamateA375 Cellular Proliferation Assay

A375 is a melanoma cell line that harbors the B-Raf V600E mutation.A375-luc cells engineered to express luciferase is plated to 384-wellwhite clear bottom plates as 1,500 cells/50 μL/well in DMEM containing10% FBS. Test compounds, dissolved in 100% DMSO at appropriateconcentrations, are transferred to the cells by a robotic Pin Tool (100mL). The cells are incubated for 2 days at 25° C., then 25 μL ofBrightGlo™ is added to each well and the plates are read byluminescence. The concentration of each compound for 50% inhibition(IC₅₀) is calculated by non-linear regression using XL Fit data analysissoftware. wild type and V600E B-Raf.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

What is claimed is:
 1. A compound of Formula I or II

wherein: R1 is (C1-C3)alkyl optionally substituted with cyano, —C(O)NH2,or hydroxy, or R1 is —X1NHC(O)OR1a or —X1NHC(O)NHR1a, where X1 is(C1-C4)alkylene optionally substituted with 1 to 3 groups eachindependently selected from (C1-C4)alkyl andhalosubstituted(C1-C4)alkyl, and R1a is (C1-C4)alkyl orhalosubstituted(C1-C4)alkyl; R1b is H or methyl; R2 is H or halogen; R3is H, halogen, (C1-C4)alkoxy, (C1-C4)alkyl,halosubstituted(C1-C4)alkoxy, or halosubstituted(C1-C4)alkyl; R4 ishalogen, H, or (C1-C4)alkyl; R5 is (C1-C6)alkyl, (C3-C6)cycloalkyl,(C3-C8)branched alkyl, halosubstituted(C1-C6)alkyl, orhalosubstituted(C3-C8)branched alkyl; R6 is H, (C1-C4)alkyl, or halogen;and R7 is (C1-C6)alkyl, (C3-C6)cycloalkyl, 1-methyl-(C3-C6)cycloalkyl,or (C3-C8)branched alkyl; or a pharmaceutically acceptable salt thereof.2. The compound of claim 1 wherein said compound is a compound ofFormula I; or a pharmaceutically acceptable salt thereof.
 3. Thecompound of claim 1, wherein: R1 is —X1NHC(O)OR1a, where X1 is a(C1-C4)alkylene optionally substituted with 1 to 3 groups eachindependently selected from (C1-C4)alkyl or halosubstituted(C1-C4)alkyland R1a is (C1-C2)alkyl or halosubstituted(C1-C2)alkyl; R2 is H or F; R3is H, halogen, (C1-C2)alkoxy, (C1-C2)alkyl,halosubstituted(C1-C2)alkoxy, or halosubstituted(C1-C2)alkyl; R4 is H ormethyl; R5 is (C1-C4)alkyl, (C3-C6)cycloalkyl, (C3-C5)branched alkyl,halosubstituted(C1-C4)alkyl, or halosubstituted(C3-C6)branched alkyl;and R7 is (C3-C6)cycloalkyl, 1-methyl-(C3-C6)cycloalkyl, or(C3-C6)branched alkyl; or a pharmaceutically acceptable salt thereof. 4.The compound of claim 2, wherein: R1 is —X1NHC(O)OR1a, where X1 is a(C1-C4)alkylene optionally substituted with 1 to 3 groups eachindependently selected from (C1-C4)alkyl or halosubstituted(C1-C4)alkyland R1a is (C1-C2)alkyl or halosubstituted(C1-C2)alkyl; R2 is H or F; R3is H, halogen, (C1-C2)alkyl, or halosubstituted(C1-C2)alkyl; R4 is H ormethyl; R5 is (C1-C4)alkyl, (C3-C6)cycloalkyl,halosubstituted(C1-C4)alkyl, or (C3-C5)branched alkyl; R6 is H,(C1-C2)alkyl, or halogen; and R7 is (C3-C6)cycloalkyl,1-methyl-(C3-C6)cycloalkyl, or (C3-C6)branched alkyl; or apharmaceutically acceptable salt thereof.
 5. The compound of claim 4,wherein: R1 is —X1NHC(O)OR1a, where X1 is (C1-C2)alkylene substitutedwith (C1-C2)alkyl and R1a is (C1-C2)alkyl; R2 is H; R3 is H, Cl, F, ormethyl; R4 is H; R5 is methyl, cyclopropyl, ethyl, propyl, isopropyl,sec-butyl, isobutyl, trifluoromethyl, or 3,3,3-trifluoropropyl; R6 is H,methyl, F, or Cl; and R7 is t-butyl, cyclopropyl, or1-methylcyclopropyl; or a pharmaceutically acceptable salt thereof. 6.The compound of claim 1 wherein R1 has the following formula (1a)

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim5 wherein R1 has the following formula (1a)

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1 wherein said compound is a compound of Formula I

wherein R1 is —X1NHC(O)OR1a, where X1 is (C1-C4)alkylene optionallysubstituted with 1 to 3 groups each independently selected from halo,(C1-C4)alkyl, and halosubstituted(C1-C4)alkyl, and R1a is H,(C1-C4)alkyl, or halosubstituted(C1-C4)alkyl; R2 is H or halogen; R3 ishalogen, (C1-C4)alkyl, or halosubstituted(C1-C4)alkyl; R4 is H, or(C1-C4)alkyl; R5 is (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C8)branchedalkyl, or halosubstituted(C1-C6)alkyl; R6 is halogen; and R7 is(C1-C6)alkyl, (C3-C6)cycloalkyl, 1-methyl-(C3-C6)cycloalkyl, or(C3-C8)branched alkyl; or a pharmaceutically acceptable salt thereof. 9.The compound of claim 1 wherein said compound is a compound of FormulaII; or a pharmaceutically acceptable salt thereof.
 10. The compound ofclaim 9 wherein R2 is H or F; R3 is halogen; R4 is H or methyl; R5 is(C1-C4)alkyl, (C3-C6)cycloalkyl, (C3-C5)branched alkyl, orhalosubstituted(C1-C4)alkyl; R6 is (C1-C2)alkyl, or halogen; and R7 is(C3-C6)cycloalkyl, 1-methyl-(C3-C6)cycloalkyl, or (C3-C6)branched alkyl;or a pharmaceutically acceptable salt thereof.
 11. The compound of claim10 wherein R2 is H; R3 is Cl or F; R4 is H; R5 is methyl, cyclopropyl,ethyl, propyl, isopropyl, sec-butyl, isobutyl, trifluoromethyl, or3,3,3-trifluoropropyl; R6 is F or Cl; and R7 is t-butyl, cyclopropyl, or1-methylcyclopropyl; or a pharmaceutically acceptable salt thereof. 12.The compound of claim 11, wherein R5 is methyl, ethyl, or cyclopropyl.13. The compound of claim 1 selected from the group consisting of(S)-Methyl1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(2-cyclopropyl-4-(2-fluoro-5-methyl-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(2-cyclopropyl-4-(2,5-dichloro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(4-(2-chloro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(2-cyclopropyl-4-(2-fluoro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;Methyl(2S)-1-(4-(2-cyclopropyl-4-(2,5-difluoro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;and (S)-Methyl1-(4-(4-(2-chloro-5-methyl-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;or a pharmaceutically acceptable salt thereof.
 14. A compound selectedfrom the group consisting of (S)-Methyl1-(4-(5-(5-chloro-2-fluoro-3-(3,3,3-trifluoropropylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(5-(5-chloro-3-(cyclopropylmethylsulfonamido)-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;(S)-Methyl1-(4-(4-(2-chloro-3-(ethylsulfonamido)-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;and (S)-Methyl1-(4-(4-(2-chloro-3-(cyclopropanesulfonamido)-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising a compound of claim 1 and a diluent, carrier orexcipient.
 16. The pharmaceutical composition of claim 15, furthercomprising an additional therapeutic agent, wherein said additionaltherapeutic agent is selected from the group consisting of an anticancercompound, an analgesic, an antiemetic, an antidepressant, and ananti-inflammatory agent.